Tricyclic 6-alkylidene-penems as beta-lactamase inhibitors

ABSTRACT

The present invention provides a compound of formula I, pharmaceutical compositions and the use thereof for the treatment of bacterial infection or disease in a patient in need thereof.

[0001] This application claims priority from copending provisionalapplication Serial No. 60/377,051, filed May 1, 2002, the entiredisclosure of which is hereby incorporated by reference.

FIELD OF INVENTION

[0002] This invention relates to certain tricyclic 6-alkylidene penemswhich act as a broad spectrum β-lactamase inhibitors. β-Lactamaseshydrolyze β-lactam antibiotics, and as such serve as the primary causeof bacterial resistance. The compounds of the present invention whencombined with β-lactam antibiotics will provide an effective treatmentagainst life threatening bacterial infections.

BACKGROUND OF THE INVENTION

[0003] Penicillins and cephalosporins are the most frequently and widelyused β-lactam antibiotics in the clinic. However, the development ofresistance to β-lactam antibiotics by different pathogens has had adamaging effect on maintaining the effective treatment of bacterialinfections. (Coleman, K. Expert Opin. Invest. Drugs 1995, 4, 693;Sutherland, R. Infection 1995, 23 (4) 191; Bush, K, Cur. Pharm. Design1999, 5, 839-845). The most significant known mechanism related to thedevelopment of bacterial resistance to the β-lactam antibiotics is theproduction of class-A, class-B and class-C serine β-lactamases. Theseenzymes degrade the β-lactam antibiotics, resulting in the loss ofantibacterial activity. Class-A enzymes preferentially hydrolyzepenicillins where as Class-C lactamases have a substrate profilefavoring cephalosporin hydrolysis. (Bush, K.; Jacoby, G. A.; Medeiros,A. A. Antimicrob. Agents Chemother. 1995, 39, 1211). To date over 250different β-lactamases have been reported (Payne, D. J,: Du, W andBateson, J. H. Exp. Opin. Invest. Drugs 2000, 247) and there is a needfor a new generation of broad spectrum β-lactamase inhibitors. Bacterialresistance to these antibiotics could be greatly reduced byadministering the β-lactam antibiotic in combination with a compoundwhich inhibits these enzymes.

[0004] The commercially available β-lactamase inhibitors such asclavulanic acid, sulbactam and tazobactam are all effective againstclass-A producing pathogens. Clavulanic acid is clinically used incombination with amoxicillin and ticarcillin; similarly sulbactam withampicillin and tazobactam with piperacillin. However, these compoundsare ineffective against class C producing organisms. The mechanism ofinactivation of class-A β-lactamases (such as PCI and TEM-1) has beenelucidated. (Bush, K.; Antimicrob. Agents Chemother. 1993, 37, 851;Yang, Y.; Janota, K.; Tabei, K.; Huang, N.; Seigal, M. M.; Lin, Y. I.;Rasmussen, B. A. and Shlaes, D. M. J. Biol. Chem. 2000, 35,26674-26682).

[0005] In 1981, the Beecham group disclosed 6-alkylidine penems ofgeneral structure 1 as inhibitors of β-lactamases. [N. F. Osborne, U.S.Pat. No. 4,485,110 (1984); N. F. Osborne, Eur. Pat. Appl. 81 301683.9.]

[0006] R₁ and R₂ are independently hydrogen or a C₁₋₁₀ hydrocarbon groupor mono heterocyclic, and R₃ represents a hydrogen or an organic group.Subsequently, the same group disclosed compounds of the general formula1, wherein R₁ comprises a 1,2,3-triazole moiety. [N. F. Osborne, Eur.Pat. Appl. 84301255.0]. The following year, the same group filed threepatent applications of the structure 1, wherein R₁ is an optionallysubstituted six membered or five membered mono aromatic ring system. [N.F. Osborne, Eur. Pat. Appl. 85100520.7; Eur. Pat. Appl. 85100521.5 andEur. Pat. Appl. 85300456.2]. European patent application No. 86305585.1discloses the synthesis and the utility of(Z)-6-(1-methyl-1,2,3-triazol-4-ylmethylene)-penem-3-carboxylate 2 as aclass-A and class-C β-lactamase inhibitor.

[0007] Eur. Pat. Appl. 86305584.4 disclosed the preparation of compoundsof general formula 1, wherein R₁=non-aromatic heterocyclic group and aPCT application [N. J. Broom; P. D. Edwards, N. F. Osborne and S.Coulton PCT WO 87/00525] disclosing R₁=fused bicyclic hetero-aromaticgroup was published. Similarly patent applications [N. J. Broom; G.Brooks; S. Coulton, Eur. Pat. Appl. 88311786.3; N. J. Broom; G. Brooks;B. P. Clarke, Eur. Pat. Appl. 88311787.1) disclosed the preparation anduse of compounds of general structure 1, wherein R₁ is a substitutedfive membered hetero-aromatic ring. A process for the preparation ofcompounds of general formula 1 has been disclosed by Coulton, et al. [S.Coulton; J. B. Harbridge; N. F. Osborne and G. Walker Eur. Pat. Appl. No87300193.7]

[0008] In the year 1993, Beecham disclosed [A. V. Stachulski and R.walker, PCT WO 93/03042] the preparation and the use of compounds ofgeneral formula 1, in which R₁=(C₁₋₆) alkyl and R₂=CH₂X or COY whereinX=halogen or CONR₂.

[0009] During the last decade three patents have been filed by Beechamdescribing compounds of general formula 3. [N. J. Broom; F. P.Harrington, PCT WO 94/10178; K. Coleman; J. E. Neale PCT WO 95/28935; K.Coleman; J. E. Neale PCT WO 95/17184] wherein R_(a)=hydrogen or anorganic group, and R_(d) and R_(e) may be both hydrogen or one or moresubstituents replacing hydrogen atoms in the ring system shown below.

BRIEF SUMMARY OF THE INVENTION

[0010] The present invention relates to novel, low molecular weightbroad spectrum β-lactam compounds and in particular to a class oftricyclic heteroaryl substituted 6-alkylidene penems which haveβ-lactamase inhibitory and antibacterial properties. The compounds aretherefore useful in the treatment of antibacterial infections in humansor animals, either alone or in combination with other antibiotics.

[0011] In accordance with the present invention there are providedcompounds of general formula I or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof:

[0012] wherein:

[0013] One of A and B denotes hydrogen and the other an optionallysubstituted fused tricyclic heteroaryl group;

[0014] X is S or O, preferably S;

[0015] R₅ is H, an in vivo hydrolyzable ester such as C1-C6 alkyl, C5-C6cycloalkyl, CHR₃OCOC1-C6 or salts such as Na, K, Ca; and

[0016] R₃ is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl.

DETAILED DESCRIPTION OF THE INVENTION

[0017] In accordance with the present invention there are providedcompounds of general formula I or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof:

[0018] wherein:

[0019] One of A and B denotes hydrogen and the other an optionallysubstituted fused tricyclic heteroaryl group;

[0020] X is S or O, preferably S;

[0021] R₅ is H, an in vivo hydrolyzable ester such as C1-C6 alkyl, C5-C6cycloalkyl, CHR₃OCOC1-C6 or salts such as Na, K, Ca; preferable R₅groups are H or salts.

[0022] The expression “Fused tricyclic heteroaryl group” is used in thespecification and claims to mean:

[0023] a group comprising three fused rings in which at least one ringhas aromatic character (i.e meets Huckel's rule (4n+2)). The fusedtricyclic heteroaryl group contains 1-6 heteroatoms selected from thegroup consisting of O, S, N and N—R₁. The fused tricyclic heteroarylmust be bonded through a carbon preferably in one of the at least onearomatic rings to the remainder of the formula I molecule. The fusedtricyclic heteroaryl group may contain 1-3 aromatic rings and 0-2non-aromatic rings.

[0024] Each aromatic ring(s) in the fused tricyclic heteroaryl group maycontain 5 to 7 ring atoms (including the bridgehead atoms) selected fromCR₂, O, S, N, and N—R₁. Each of the aromatic ring(s) of the fusedtricyclic heteroaryl group may contain 0 to 3 heteroatoms selected fromO, S, N or N—R₁. The non-aromatic ring(s), if any, of the fusedtricyclic heteroaryl group may contain 5-8 ring atoms (includingbridgehead atoms) and contain 0-4 heteroatoms selected from N,N—R₁, O orS(O)_(n), wherein n is 0-2. In each non-aromatic ring of the fusedtricyclic heteroaryl group, one or two of the non-bridgehead carbonatoms may each be optionally substituted with one or two R₄, and each R₄may be independently the same or different. Examples of fused tricyclicheteroaryl are optionally substituted ring systems such asimidazo[2,1-b][1,3]benzothiazole optionally substituted e.g., by forexample C1-C6alkyl, C1-C6alkoxy or halo (such as chlorine or fluorine);imidazo[1,2-a]quinoline;6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazole;imidazo[1,2-a]quinoxaline;5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinedibenzo[b,f][1,4]-oxazepin-11 (10H)-one optionally substituted e.g., byarylalkyl such as benzyl; 7,8-dihydro-6H-3,4,8b-triaza-as-indaceneoptionally substituted by C1-C6 alkoxy; 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepine optionally substituted e.g., byC1-C6 alkoxy; 5H-Imidazo[2,1-a]isoindole;5,8-dihydro-6H-imidazo[2,1]-b]pyrano[4,3-d][, 3]thiazole;imidazo[2,1-b]benzothiazole; [1,3]thiazolo[3,2-a]benzimidazole;7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazole;5,6,7,8-tetrahydroimidazo[2,1-b][1,3]-benzothiazole;9H-imidazo[1,2-a]benzimidazole optionally substituted e.g., byC1C6alkyl; 4H-thieno[2′,3′:4,5]thiopyrano[2,3-b]pyridine;7,8-dihydro-6H-cyclopenta[e][1,2,4]-triazolo[1,5-a]pyrimidine optionallysubstituted e.g., by C1-C6alkyl;6,7,8,9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidineoptionally substituted e.g., by C2-C7alkoxycarbonyl;8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolo[1,5-a]-quinazoline;6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazoline optionallysubstituted e.g., by C1-C6alkyl;7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidine optionallysubstituted e.g., by C1-C6alkoxy;7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidinyl optionallysubstituted e.g., by arylalkyloxyalkyloxy;3-dihydro[1,3]thiazolo[3,2-a]-benzimidazole;2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole;4-dihydro-2H-[1,3]thiazino[3,2-a]-benzimidazole;[1,3]thiazolo[3,2-a]benzimidazole;7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]-oxazole;5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole; and5,6,7,8-tetrahydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridineoptionally substituted e.g., by C2-C7alkoxycarbonyl.

[0025] R₁ is H, optionally substituted —C1-C6 alkyl, optionallysubstituted -aryl, optionally substituted -heteroaryl or mono orbicyclic saturated heterocycles, optionally substituted —C3-C7cycloalkyl, optionally substituted —C3-C6 alkenyl, optionallysubstituted —C3-C6 alkynyl with the proviso that both the double bondand the triple bond should not be present at the carbon atom which isdirectly linked to N; optionally substituted —C1-C6 per fluoro alkyl,—S(O)_(p) optionally substituted alkyl or aryl where p is 2, optionallysubstituted —C═Oheteroaryl, optionally substituted —C═Oaryl, optionallysubstituted —C═O(C1-C6) alkyl, optionally substituted —C═O(C3-C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkyl aryl, optionallysubstituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionallysubstituted C1-C6 alkyl mono or bicyclic saturated heterocycles,optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR₆R₇,—SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl, optionallysubstituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkyl aryloxy alkylamines,optionally substituted alkoxy carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heteroaryloxy carbonyl. Preferred R₁groups are H, optionally substituted alkyl, optionally substituted aryl,—C═O(C1-C6)alkyl, C3-C6alkenyl, C3-C6alkynyl, optionally substitutedcycloalkyl, SO₂alkyl, SO₂aryl, optionally substituted heterocycles,—CONR₆R₇, and optionally substituted heteroaryl.

[0026] R₂ is hydrogen, optionally substituted C1-C6 alkyl, optionallysubstituted C2-C6 alkenyl having 1 to 2 double bonds, optionallysubstituted C2-C6 alkynyl having 1 to 2 triple bonds, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkyl aryloxy alkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted C1-C6 alkylaryl, optionally substituted arylalkyl,optionally substituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, optionally substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedalkylaryloxyalkylamines, optionally substituted C3-C7 cycloalkyl,optionally substituted C3-C7 saturated or partially saturatedheterocycle. Preferred R₂ groups are H, optionally substituted alkyl,optionally substituted alkoxy, optionally substituted heteroaryl,halogen, CN, hydroxy, optionally substituted heterocycle, —CONR₆R₇,COOR₆, optionally substituted aryl, S(O)_(q)-alkyl, and S(O)_(q)-aryl.

[0027] R₃ is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl. Preferred R₃ groupsare H or C1-C6 alkyl.

[0028] R₄ is H, optionally substituted C1-C6 alkyl, one of R₄ is OH,C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆, —NR₆R₇, —CONR₆R₇; or R₄R₄ maytogether be ═O or R₄R₄ together with the carbon to which they areattached may form a spiro system of five to eight members with orwithout the presence of heteroatoms selected N, O, S═(O)n (where n=0 to2), N—R₁; preferred R₄ groups are H, C1-C6 alkyl, NR₆R₇, or R₄R₄together with the carbon to which they are attached forming a spirosystem of five to eight members.

[0029] R₆ and R₇ are independently H, optionally substituted C1-C6alkyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C1-C6 alkyl aryl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted C1-C6 alkyl heteroaryl, R₆ and R₇ can together with thenitrogen to which they are attached form a 3-7 membered saturated ringsystem optionally having one or two heteroatoms such as N—R₁, O,S═(O)_(n) n=0-2. Preferred R₆ and R₇ groups are H, C1-C6 alkyl,arylalkyl, heteroarylalkyl, or R₆ and R₇ together with the nitrogen towhich they are attached forming a 3-7 membered saturated ring system.

[0030] Chemical Definitions

[0031] The term alkyl means both straight and branched chain alkylmoieties of 1-12 carbons, preferably of 1-6 carbon atoms.

[0032] The term alkenyl means both straight and branched alkenylmoieties of 2-8 carbon atoms containing at least one double bond, and notriple bond, preferably the alkenyl moiety has 1 or two double bonds.Such alkenyl moieties may exist in the E or Z conformations; thecompounds of this invention include both conformations. In the case ofalkenyl, hetero atoms such as O, S or N—R₁ should not be present on thecarbon that is bonded to a double bond;

[0033] The term alkynyl includes both straight chain and branchedalkynyl moieties containing 2-6 carbon atoms containing at least onetriple bond, preferably the alkynyl moiety has one or two triple bonds.In the case of alkynyl, hetero atoms such as O, S or N—R₁ should not bepresent on the carbon that is bonded to a double or triple bond;

[0034] The term cycloalkyl refers to a alicyclic hydrocarbon grouphaving 3-7 carbon atoms. The term perfluoroalkyl is used herein to referto both straight- and branched-chain saturated aliphatic hydrocarbongroups having at least one carbon atom and two or more fluorine atoms.Examples include CF₃, CH₂CF₃, CF₂CF₃ and CH(CF₃)₂. The term halogen isdefined as Cl, Br, F, and I.

[0035] If alkyl, alkenyl, alkynyl, or cycloalkyl is “optionallysubstituted”, one or two of the following are possible substituents:nitro, -aryl, -heteroaryl, alkoxycarbonyl-, -alkoxy, -alkoxy-alkyl,alkyl-O-C2-C4alkyl-O—, -cyano, -halogen, -hydroxy, —N—R₆R₇,-trifluoromethyl, -trifluoromethoxy, arylalkyl, alkylaryl, R₆R₇N-alkyl-,HO-C1-C6-alkyl-, alkoxyalkyl-, alkyl-S—, —SO₂N—R₆R₇, —SO₂NHR₆, —CO₂H,CONR₆R₇, aryl-O—, heteroaryl-O—, —S(O)_(s)-aryl (where s=0-2),-alkyl-O-alkyl-NR₆R₇, -alkyl-aryl-O-alkylN-R₆R₇, C1-C6alkyl, alkenyl,alkynyl, cycloalkyl, alkoxy-alkyl-O—, R₆R₇N-alkyl-, and—S(O)_(s)-heteroaryl (where s=0-2); Preferred substitutents for alkyl,alkenyl, alkynyl, and cycloalkyl include: halogen, nitro, aryl,heteroaryl, alkoxycarbonyl-, alkoxy, -alkoxy-alkyl, -cyano, hydroxy, and—N—R₆R₇.

[0036] Aryl is defined as an aromatic hydrocarbon moiety selected fromthe group: phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl,tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl,groups.

[0037] Heteroaryl is defined as a aromatic heterocyclic ring system(monocyclic or bicyclic) where the heteroaryl moieties are selectedfrom: (1) furan, thiophene, indole, azaindole, oxazole, thiazole,isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine,pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole,N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole,1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole,benzothiazole, benzofuran, benzisoxazole, benzimidazole,N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline,quinoline, and isoquinoline; (2) a bicyclic aromatic heterocycle where aphenyl, pyridine, pyrimidine or pyridizine ring is: (a) fused to a6-membered aromatic (unsaturated) heterocyclic ring having one nitrogenatom; (b) fused to a 5 or 6-membered aromatic (unsaturated) heterocyclicring having two nitrogen atoms; (c) fused to a 5-membered aromatic(unsaturated) heterocyclic ring having one nitrogen atom together witheither one oxygen or one sulfur atom; or (d) fused to a 5-memberedaromatic (unsaturated) heterocyclic ring having one heteroatom selectedfrom O, N or S.

[0038] If aryl or heteroaryl is ‘optionally substituted’, one or two ofthe following are possible substituents: nitro, -aryl, -heteroaryl,alkoxycarbonyl-, -alkoxy, -alkoxy-alkyl, alkyl-O-C2-C4alkyl-O—, -cyano,-halogen, -hydroxy, —N—R₆R₇, -trifluoromethyl, -trifluoromethoxy,arylalkyl, alkylaryl, R₆R₇N-alkyl-, HO-C1-C6-alkyl-, alkoxyalkyl-,alkyl-S—, —SO₂N—R₆R₇, —SO₂NHR₆, —CO₂H, CONR₆R₇, aryl-O—, heteroaryl-O—,—S(O)_(s)-aryl (where s=0-2), -alkyl-O-alkyl-NR₆R₇,-alkyl-aryl-O-alkylN-R₆R₇, C1-C6alkyl, alkenyl, alkynyl, cycloalkyl,alkoxy-alkyl-O—, R₆R₇N-alkyl-, and —S(O)_(s)-heteroaryl (where s=0-2);Preferred substituents for aryl and heteroaryl include: alkyl, halogen,—N—R₆R₇, trifluoromethyl, -trifluoromethoxy, arylalkyl, and alkylaryl.

[0039] Arylalkyl is defined as Aryl-C1-C6alkyl-; Arylalkyl moietiesinclude benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,2-phenylpropyl and the like. The term ‘optionally substituted’ refers tounsubstituted or substituted with 1 or 2 substituents on the alkyl oraryl moiety as defined above.

[0040] Alkylaryl is defined as C1-C6alkyl-aryl-. The term ‘optionallysubstituted’ refers to unsubstituted or substituted with 1 or 2substituents on the aryl or alkyl moiety as defined above.

[0041] Heteroaryl-C1-C6-alkyl is defined as a heteroaryl substitutedalkyl moiety wherein the alkyl chain is 1-6 carbon atoms (straight orbranched). Alkyl heteroaryl moieties include Heteroaryl-(CH₂)₁₋₆— andthe like. The term ‘optionally substituted’ refers to unsubstituted orsubstituted with 1 or 2 substituents on the alkyl or heteroaryl moietyas defined above;

[0042] C1-C6 alkylheteroaryl is defined an alkyl chain of 1-6 carbonatoms (straight or branched) attached to a heteroaryl moiety, which isbonded to the rest of the molecule. Ex. C1-C6-alkyl-Heteroaryl-. Theterm ‘optionally substituted’ refers to unsubstituted or substitutedwith 1 or 2 substituents on the alkyl or heteroaryl moiety as definedabove;

[0043] Saturated or partially saturated heterocycles groups are definedas heterocyclic rings selected from the moieties; aziridinyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl,dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,dihydro-1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydroquinolinyl, and tetrahydroisoquinolinyl

[0044] C1-C6 alkyl mono or bicyclic saturated or partially saturatedheterocycles is defined as an alkyl group (straight or branched) ofC1-C6 attached to a heterocycles (which is defined before) through acarbon atom or a nitrogen atom and the other end of the alkyl chainattached to the rest of the molecule. The terms ‘optionally substituted’refers to unsubstituted or substituted with 1 or 2 substituents presenton the alkyl or heterocyclic portion of the molecule, as defined before;

[0045] Arylalkyloxyalkyl is defined as Aryl-C1-C6alkyl-O-C1-C6alkyl-.The term ‘optionally substituted’ refers to unsubstituted or substitutedwith 1 or 2 substituents present on the alkyl and/or aryl portions asdefined before;

[0046] Alkyloxyalkyl is defined as C1-C6 alkyl-O-C1-C6alkyl-. The term‘optionally substituted’ refers to unsubstituted or substituted with 1or 2 substituents present at the alkyl moiety as defined before;

[0047] Aryloxyalkyl is defined as Aryl-O-C1-C6 alkyl-. The term‘optionally substituted’ refers to unsubstituted or substituted with 1or 2 substituents present at the alkyl or aryl moiety as defined before;

[0048] Heteroarylalkyloxyalkyl is defined asHeteroaryl-C1-C6alkyl-O-C1-C6alkyl-. The term ‘optionally substituted’refers to unsubstituted or substituted with 1 or 2 substituents presenton the alkyl or heteroaryl moiety as defined before;

[0049] Aryloxyaryl is defined as Aryl-O-Aryl-. The term ‘optionallysubstituted’ refers to unsubstituted or substituted with 1 or 2substituents present on the aryl moiety as defined before;

[0050] Aryloxyheteroaryl is defined as Aryl-O-Heteroaryl- or-Aryl-O-Heteroaryl; In this definition either the aryl moiety or theheteroaryl moiety can be attached to the remaining portion of themolecule; The term ‘optionally substituted’ refers to unsubstituted orsubstituted with 1 or 2 substituents present on the aryl moiety or onthe heteroaryl moiety as defined before;

[0051] Alkyl aryloxyaryl is defined as Aryl-O-Aryl-C1-C6alkyl-; The term‘optionally substituted’ refers to unsubstituted or substituted with 1or 2 substituents present at the aryl moiety as defined before;

[0052] Alkylaryloxyheteroaryl is defined asHeteroaryl-O-Aryl-C1-C6alkyl-; The term ‘optionally substituted’ refersto unsubstituted or substituted with 1 or 2 substituents present on thearyl moiety or on the hetroaryl moiety as defined before;

[0053] Alkylaryloxyalkylamine is defined asR₆R₇N—C1-C6alkyl-O-Aryl-C1C6alkyl-; The terms ‘optionally substituted’refers to unsubstituted or substituted with 1 or 2 substituents presenton the alkyl or aryl moiety as defined before; R₆ and R₇ as definedbefore;

[0054] Alkoxycarbonyl is defined as C1-C6alkyl-O—C═O—; The term‘optionally substituted’ refers to unsubstituted or substituted with 1or 2 substituents present on the alkyl portion of the alkoxy moiety asdefined before;

[0055] Aryloxycarbonyl is defined as Aryl-O—C═O—; The term ‘optionallysubstituted’ refers to unsubstituted or substituted with 1 or 2substituents present at the aryl moiety as defined before;

[0056] Heteroaryloxy carbonyl is defined as Heteroaryl-O—C═O—; The term‘optionally substituted’ refers to unsubstituted or substituted with 1or 2 substituents present at the heteroaryl moiety as defined before;

[0057] Alkoxy is defined as C1-C6alkyl-O—; The terms ‘optionallysubstituted’ refers to unsubstituted or substituted with 1 or 2substituents present at the alkyl moiety as defined before;

[0058] Aryloxy is defined as Aryl-O—; The term ‘optionally substituted’refers to unsubstituted or substituted with 1 or 2 substituents presentat the aryl moiety as defined before;

[0059] Heteroaryloxy is defined as Heteroaryl-O—; The term ‘optionallysubstituted’ refers to unsubstituted or substituted with 1 or 2substituents present at the heteroaryl moiety as defined before;

[0060] Alkenyloxy is defined as C3-C6 alkene-O—; Example allyl-O—,but-2-ene-O or like moieties; The term ‘optionally substituted’ refersto unsubstituted or substituted with 1 or 2 substituents present at thealkene moiety as defined before, with the proviso that no hetero atomsuch as O, S or N—R₁ is present on the carbon atom, which is attached toa double bond;

[0061] Alkynyloxy is defined as C3-C6alkyne-O—; Example CH triple bondC—CH₂—O—, or like moieties; The term ‘optionally substituted’ refers tounsubstituted or substituted with 1 or 2 substituents present at thealkyne moiety as defined before, with the proviso that no hetero atomsuch as O, S or N—R₁ is present on a carbon atom which is attached to adouble or triple bond;

[0062] Alkylaminoalkoxy is defined as R₆R₇N—C1-C6-alkyl-O-C1-C6-alkyl-,where the terminal alkyl group attached to the oxygen is connected tothe rest of the molecule; The terms R₆ and R₇ are defined above; Theterm ‘optionally substituted’ refers to unsubstituted or substitutedwith 1 or 2 substituents present at the alkyl moiety as defined before;

[0063] Alkylenedioxy is defined as —O—(CH₂)₂—O—;

[0064] Aryloxyalkylamine is defined as R₆R₇N-C1-C6-alkyl-O-Aryl-, wherethe aryl is attached to the rest of the molecule; The term ‘optionallysubstituted’ refers to unsubstituted or substituted with 1 or 2substituents present at the alkyl or aryl moiety as defined before;

[0065] Arylalkenyl is defined as Aryl-C2-C8alkene-, with the provisothat no hetero atom such as O, S or N—R₁ is present on the carbon atom,which is attached to a double bond; The term ‘optionally substituted’refers to unsubstituted or substituted with 1 or 2 substituents presenton the alkene or aryl moiety as defined before;

[0066] Heteroaryloxyalkyl is defined as Heteroaryl-O-C1-C6alkyl-; Theterm ‘optionally substituted’ refers to unsubstituted or substitutedwith 1 or 2 substituents present at the heteroaryl moiety as definedbefore;

[0067] Heteroaryloxyaryl is defined as Heteroaryl-O-aryl-, where thearyl moiety is attached to the rest of the molecule; The term‘optionally substituted’ refers to unsubstituted or substituted with 1or 2 substituents present at the heteroaryl moiety or the aryl moiety asdefined before;

[0068] Alkoxy, alkoxyalkyl, alkoxyalkyloxy and alkylthioalkyloxy aremoieties wherein the alkyl chain is 1-6 carbon atoms (straight orbranched). Aryloxy, heteroaryloxy, arylthio and heteroarylthio aremoieties wherein the aryl and heteroaryl groups are as herein beforedefined. Arylalkyloxy, heteroarylalkyloxy, arylalkylthio andheteroarylalkylthio are moieties wherein the aryl and heteroaryl groupsare as herein before defined and wherein the alkyl chain is 1-6 carbons(straight or branched). Aryloxyalkyl, heteroaryloxyalkyl,aryloxyalkyloxy and heteroaryloxyalkyloxy are substituents wherein thealkyl radical is 1-6 carbon atoms. The terms monoalkylamino anddialkylamino refer to moieties with one or two alkyl groups wherein thealkyl chain is 1-6 carbons and the groups may be the same or different.The terms monoalkylaminoalkyl and dialkylaminoalkyl refer tomonoalkylamino and dialkylamino moieties with one or two alkyl groups(the same or different) bonded to the nitrogen atom which is attached toan alkyl group of 1-3 carbon atoms.

[0069] Pharmaceutically acceptable salts are those salts which may beadministered or provided to a warm blooded animal, preferably sodium,potassium or calcium alkaline earth metal salts.

[0070] Preferably the formula I compound has the followingstereochemistry:

[0071] Examples of tricyclic heteroarylgroup A and B:

[0072] Ring size and arrangements: (5-5-5)

[0073] In both formula 1-A and 1-B Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ areindependently selected from CR₂, N, O, S or N—R₁ and as mentioned aboveone of Z₁-Z₇ is a carbon atom to which the remainder of the molecule isattached. Y₁, Y₂, Y₃ and Y₄ may independently be C or N.

[0074] Ring size and arrangement: (5-5-6)

[0075] In both formula 2-A and 2-B Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ and Z₈ areindependently selected from CR₂, N. O, S or N—R₁ and as mentioned aboveone of the Z₁-Z₈ is a carbon atom to which the remainder of the moleculeis attached. Y₁, Y₂, Y₃ and Y₄ may be independently be C or N.

[0076] Ring size and arrangement: (5-6-5)

[0077] In both formula 3-A and 3-B Z₁, Z₂, Z₃, Z₄, Z₅ Z₆, Z₇ and Z₈ areindependently selected from CR₂, N, O, S or N—R₁ and as mentioned aboveone of Z₁-Z₈ is a carbon atom to which the remainder of the molecule isattached. Y₁, Y₂, Y₃ and Y₄ may be C or N.

[0078] Ring size and arrangements: (5-6-6)

[0079] In formula 4-A, 4-B and 4-C Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ and Z₈ areindependently selected from CR₂, N, O, S or N—R₁ and as mentioned aboveone of the Z₁-Z₈ is a carbon atom to which the remainder of the moleculeis attached. Y₁, Y₂, Y₃ and Y₄ are independently C or N.

[0080] Ring size and arrangements: [5-5-(non-aromatic)]

[0081] In both formula 5-A and 5-B Z₁, Z₂, Z₃ and Z₄ are indpendentlyselected from CR₂, N, O, S or N—R₁ and as mentioned above one of theZ₁-Z₄ is a carbon atom to which the remainder of the molecule isattached; Y₁, Y₂, Y₃ and Y₄ are independently C or N. W₁, W₂ and W₃ areindependently selected from CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; and t=1 to 3.

[0082] Ring size and arrangement: [5-6-(non-aromatic)]

[0083] In formulae 6-A, 6-B and 6-C Z₁, Z₂, Z₃, Z₄ and Z₅ areindepedently selected from CR₂, N, O, S or N—R₁ and as mentioned aboveone of the Z₁-Z₅ is a carbon atom to which the remainder of the moleculeis attached. Y₁, and Y₂ are independently C or N. W₁, W₂ and W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring; andt=1 to 3.

[0084] Ring size and arrangement: [5-(non-aromatic)-5]

[0085] In formulae 7-A and 7-B Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ areindependently selected from CR₂, N, O, S, and N—R₁; one of Z₁-Z₆ is acarbon atom to which the remainder of the molecule is attached. Y₁, Y₂,Y₃ and Y₄ are independently C or N. W₁ and W₂ are independently selectedfrom CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that no S—S, S—O orO—O bond formation can occur to form a saturated ring; and t=1 to 3.

[0086] Ring size and arrangement: [5-(non-aromatic)-6]

[0087] In formulae 8-A and 8-B Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ areindepdently selected from CR₂, N, O, S and N—R₁ and as mentioned aboveone of the Z₁-Z₇ is a carbon atom to which the remainder of the moleculeis attached. Y₁, Y₂, Y₃ and Y₄ are independently C or N. W₁ and W₂ areindependently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring; andt=0-3.

[0088] Ring size and arrangement [5-(non-aromatic)-(non-aromatic)]

[0089] In formulae 9-A and 9-B Z₁, Z₂ and Z₃ are independently selectedfrom CR₂ N, O, S or N—R₁; one of Z₁-Z₃ is a carbon atom to which theremainder of the molecule is attached. Y₁ and Y₄ are independently C orN; Y₂ and Y₃ are independently CH or N; W₁, W₂ W₃, W₄ and W₅ areindependently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring; t=0to 2 and u=1 to 3.

[0090] Ring size and arrangement (6-5-6)

[0091] In formula 10-A and 10-B Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ and Z₉are independently selected from CR₂, N, O, S or N—R₁ and as mentionedabove one of the Z₁-Z₉ is a carbon atom to which the remainder of themolecule is attached. Y₁, Y₂, Y₃ and Y₄ are independently C or N.

[0092] Ring size and arrangement (6-6-6)

[0093] In formula 11-A, 11-B and 11-C Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈, Z₉and Z₁₀ are independently CR₂, N, O, S or N—R₁; one of the Z₁-Z₁₀ is acarbon atom to which the remainder of the molecule is attached. Y₁, Y₂,Y₃ and Y₄ are independently C or N.

[0094] Ring size and arrangement [6-5-(non-aromatic)]

[0095] In formula 12-A and 12-B Z₁, Z₂, Z₃, Z₄ and Z₅ are independentlyCR₂, N, O, S or N—R₁ with the proviso that one of Z₁-Z₅ is a carbon atomto which the remainder of the molecule is attached. Y₁, Y₂, Y₃ and Y₄are independently C or N; W₁, W₂, W₃ are independently CR₄R₄ O, N—R₁, orS═(O)_(r) (r=0-2) with the proviso that no S—S, S—O or O—O bondformation can occur to form a saturated ring; and t=1-4.

[0096] Ring size and arrangement [6-6-(non-aromatic)]

[0097] In formula 13-A, 13-B and 13-C Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ areindependently CR₂, N, O, S or N—R₁; one of Z₁-Z₆ is a carbon atom towhich the remainder of the molecule is attached. Y₁, Y₂, Y₃ and Y₄ areindependently C or N; W₁, W₂ and W₃ are independently CR₄R₄, S(O)r(r=0-2), O, or N—R₁ with the proviso that no S—S, S—O or O—O bondformation can occur to form a saturated ring; and t=1 to 3.

[0098] Ring size and arrangement [6-(non-aromatic)-6]

[0099] In formula 14-A, 14-B and 14-C Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ and Z₈are independently CR₂, N, O, S or N—R₁; one of Z₁-Z₈ is a carbon atom towhich the remainder of the 15 molecule is attached. Y₁, Y₂, Y₃ and Y₄are independently C or N; W₁, and W₂ are independently CR₄R₄, S(O)r(r=0-2), O, or N—R₁ with the proviso that no S—S, S—O or O—O bondformation can occur to form a saturated ring; and t=1 to 2.

[0100] Ring size and arrangement [6-(non-aromatic)-(non-aromatic)]

[0101] In formula 15-A, 15—B and 15—C Z₁, Z₂, Z₃ and Z₄ areindependently CR₂, N, O, S or N—R₁; one of Z₁-Z₄ is a carbon atom towhich the remainder of the molecule is attached. Y₁, Y₂, Y₃ and Y₄ areindependently C or N; W₁, W₂, W₃, W₄ and W₅ are independently CR₄R₄,S(O)r (r=0-2), O, or N—R₁ with the proviso that no S—S, S—O or O—O bondformation can occur to form a saturated ring; t=1 to 3 and u=1 to 3.

[0102] The preferred embodiments of formula 1-A are:

[0103] 1. Z₁ is O, S, or N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ areindependently CR₂, or N; Y₁, Y₂, Y₃, Y₄ are C; any one of Z₂, Z₃, Z₄,Z₅, Z₆, Z₇ is a carbon to which the remainder of the molecule isattached.

[0104] 2. Z₁ is O, S, or N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ areindependently CR₂; Y₁, Y₂, Y₃, and Y₄ are C; one of Z₂, Z₃, Z₄, Z₅, Z₆,Z₇ is a carbon to which the remainder of the molecule is attached.

[0105] 3. Z₂ is O, S, or N—R₁; Z₁, Z₃, Z₄, Z₅, Z₆ and Z₇ areindependently CR₂, or N; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₃, Z₄, Z₅,Z₆, Z₇ is a carbon to which the remainder of the molecule is attached.

[0106] 4. Z₂ is O, S, or N—R₁; Z₁, Z₃, Z₄, Z₅, Z₆ and Z₇ areindependently CR₂; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₃, Z. Z₅, Z₆, Z₇ isa carbon to which the remainder of the molecule is attached.

[0107] 5. Z₃ is O, S, or N—R₁; Z₁, Z₂, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂, or N; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₂, Z₄, Z₅, Z₆, Z₇ is acarbon to which the remainder of the molecule is attached.

[0108] 6. Z₃ is O, S, or N—R₁; Z₁, Z₃, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₃, Z₄, Z₅, Z₆, or Z₇ is a carbonto which the remainder of the molecule is attached.

[0109] 7. Z₇ is O, S, or N—R₁; Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ areindependently CR₂ or N; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₂, Z₃, Z₄, Z₅and Z₆ is a carbon to which the remainder of the molecule is attached.

[0110] 8. Z₇ is O, S, or N—R₁; Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ areindependently CR₂; Y₁, Y₂, Y₃, Y₄ are C; any of Z₁, Z₂, Z₃, Z₄, Z₅ andZ₆ is a carbon to which the remainder of the molecule is attached.

[0111] 9. Z₁, Z₄, and Z₆ are independently O, S, or N—R₁; Z₂, Z₃, Z₅, Z₇are independently CR₂, or N; Y₁, Y₂, Y₃, Y₄ are C; any one of Z₂, Z₃,Z₅, or Z₇ is a carbon to which the remainder of the molecule isattached.

[0112] 10. Z₁, Z₄, and Z₆ are independently O, S, or N—R₁; Z₂, Z₃, Z₅,Z₇ are independently CR₂; Y₁, Y₂, Y₃, Y₄ are C; any one of Z₂, Z₃, Z₅,or Z₇ is a carbon to which the remainder of the molecule is attached.

[0113] 11. Z₃, Z₄, and Z₆ are independently O, S, or N—R₁; Z₁, Z₂, Z₅,Z₇ are independently CR₂, or N; Y₁, Y₂, Y₃, Y₄ are C; any one of Z₁, Z₂,Z₅, or Z₇ is a carbon to which the remainder of the molecule isattached.

[0114] 12. Z₃, Z₄, and Z₆ are independently O, S, or N—R₁; Z₂, Z₃, Z₅,Z₇ are independently CR₂; Y₁, Y₂, Y₃, Y₄ are C; any one of Z₁, Z₂, Z₅,or Z₇ is a carbon to which the remainder of the molecule is attached.

[0115] 13. Z₁ is O, S, or N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ areindependently CR₂, or N; Y₂ is N; Y₁, Y₃, Y₄ are C; any one of Z₂, Z₃,Z₄, Z₅, Z₆, or Z₇ is a carbon to which the remainder of the molecule isattached.

[0116] 14. Z₁ is O, S, or N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ areindependently CR₂; Y₂ is N; Y₁, Y₃, Y₄ are C; one of Z₂, Z₃, Z₄, Z₅, Z₆,or Z₇ is a carbon to which the remainder of the molecule is attached.

[0117] 15. Z₂ and Z are independently O, S, or N—R₁; Z₁, Z₃, Z₅, Z₆, Z₇are independently CR₂, N; Y₁ is N; Y₂, Y₃, Y₄ are C; any one of Z₁, Z₃,Z₅, Z₆, or Z₇ is a carbon to which the remainder of the molecule isattached.

[0118] 16. Z₂ and Z₄ are independently O, S, or N—R₁; Z₁, Z₃, Z₅, Z₆, Z₇are independently CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; any one of Z₁, Z₃, Z₅,Z₆, or Z₇ is a carbon to which the remainder of the molecule is attached

[0119] 17. Z₃ and Z₅ are independently O, S, or N—R₁; Z₁, Z₂, Z₄, Z₆, Z₇are independently CR₂, or N; Y₁ is N; Y₂, Y₃, Y₄ are C; any one of Z₁,Z₃, Z₅, Z₆, or Z₇ is a carbon to which the remainder of the molecule isattached.

[0120] 18. Z₃ and Z₅ are independently O, S, or N—R₁; Z₁, Z₂, Z₄, Z₆, Z₇are independently CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; any one of Z₁, Z₃, Z₅,Z₆, or Z₇ is a carbon to which the remainder of the molecule isattached.

[0121] 19. Z₁ and Z₅ are independently O, S, or N—R₁; Z₂, Z₃, Z₄, Z₆, Z₇are independently N, or CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; any one of Z₂,Z₃, Z₄, Z₆, Z₇ is a carbon to which the remainder of the molecule isattached.

[0122] 20. Z₁ and Z₅ are independently O, S, or N—R₁; Z₂, Z₃, Z₄, Z₆, Z₇are independently CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; any one of Z₂, Z₃, Z,Z, or Z₇ is a carbon to which the remainder of the molecule is attached.

[0123] 21. Z₃ and Z₇ are independently O, S, or N—R₁; Z₁, Z₂, Z₄, Z₅, Z₆are independently N, or CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; any one of Z₁,Z₂, Z₄, Z₅, or Z₆ is a carbon to which the remainder of the molecule isattached.

[0124] 22. Z₃ and Z₇ are independently O, S, N—R₁; Z₁, Z₂, Z₅, Z₆ areindependently CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; Any one of Z₁, Z_(2, 4),Z₅, or Z₆ is a carbon to which the remainder of the molecule isattached.

[0125] 23. Z₃ and Z₇ are independently O, S, N—R₁; Z₁, Z₂, Z₄, Z₅, Z₆are independently N, or CR₂; Y₂ is N; Y₁, Y₃, Y₄ are C; any one of Z₁,Z₂, Z₄, Z₅, or Z₆ is a carbon to which the remainder of the molecule isattached.

[0126] 24. Z₃ and Z₇ are independently O, S, or N—R₁; Z₁, Z₂, Z₄, Z₅, Z₆are independently CR₂; Y₂ is N; Y₁, Y₃, Y₄ are C; any one of Z₁, Z₂, Z₄,Z₅, or Z₆ is a carbon to which the remainder of the molecule isattached.

[0127] 25. Z₃ and Z₅ are independently O, S, N—R₁; Z₁, Z₂, Z₄, Z₆, Z₇are independently N, or CR₂; Y₂ is N; Y₁, Y₃, Y₄ are C; any one of Z₁,Z₂, Z₆, or Z₇ is a carbon to which the remainder of the molecule isattached.

[0128] 26. Z₃ and Z₅ are independently O, S, or N—R₁; Z₁, Z₂, Z₄, Z₆, Z₇are independently CR₂; Y₂ is N; Y₁, Y₃, Y₄ are C; any one of Z₁, Z₂, Z₃,Z₆, or Z₇ is a carbon to which the remainder of the molecule isattached.

[0129] The preferred embodiment of formula 1-B is:

[0130] 27. Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ are independently CR₂.

[0131] The preferred embodiments of formula 2-A are:

[0132] 28. Z₁ is CR₂; Z₂ is the carbon to which the remainder of themolecule is attached; Z₃ is N or CR₂; Z is O, S, CR₂ or N—R₁; Z₅, Z₆,Z₇, Z₈ are independently CR₂ or N; Y₁ is N; Y₂, Y₃ and Y₄ are C.

[0133] 29. Z₂ is CR₂; Z₁ is carbon to which the remainder of themolecule is attached; Z₃ is N or CR₂; Z₄ is O, S, CR₂ or N—R₁; Z₅, Z₆,Z₇, Z₈ are independently CR₂ or N; Y₁ is N; Y₂, Y₃ and Y₄ are C.

[0134] 30. Z₁ is N, Z₂ is carbon to which the remainder of the moleculeis attached; Z₃ is N or CR₂; Z₄ O, S, CR₂ or N—R₁; Z₅, Z₆, Z₇, Z₈ areindependently CR₂ or N; Y₁ is N; Y₂, Y₃ and Y₄ are C.

[0135] 31. Z₁, Z₂, Z₃ are independently CR₂ or N; Z is O, S, CR₂ orN—R₁; Z₅, Z₆, Z₇, Z₈ are independently CR₂ or N and one of Z₅, Z₆, Z₇,or Z₈ is a carbon to which the remainder of the molecule is attached; Y₁is N; Y₂, Y₃ and Y₄ is C.

[0136] 32. Z₁ is CR₂ or N; Z₂ is CR₂: Z₃ is O, S or N—R₁; Z₄ is N orCR₂; Z₅, Z₆, Z₇, Z₈ are independently CR₂; Y₁ is N, or C; Y₂, Y₃ and Y₄are C.

[0137] 33. Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ are independently N or CR₂;Y₁, Y₂, Y₃, Y₄ are C.

[0138] 34. Z₁, Z₂, Z₅, Z₆, Z₇, Z₈ are independently N or CR₂; Z₃ and Z₄are independently O, S, or N—R₁; Y₁, Y₂, Y₃, and Y₄ are C.

[0139] 35. Z₁, Z₂, and Z₃ are independently CR₂ or N; 4 is O, S, CR₂ orN—R₁; Z₅, Z₆, Z₇, and Z₈ are independently CR₂ or N; Y, is N; Y₂, Y₃ andY₄ are C.

[0140] 36. Z₁ is N; Z₂ is CR₂; Z₃ is the carbon atom to which remainderof the molecule is attached; Z₄ is N; Z₅, Z₆, Z₇, Z₈ are independently Nor CR₂; Y₁, Y₂, Y₃, Y₄ are independently N or C.

[0141] The preferred embodiment of formula 2-B is:

[0142] 37. Z₁ and Z₄ are independently CR₂ or N; Z₂ and Z₃ are CR₂; Z₅,Z₆, Z₇ are independently CR₂ or N; Y₁ is C and Y₂ is N.

[0143] 38. Z₁ is O, S, or N—R₁; Z₂ is CR₂; Z₃ is CR₂, or N; Z₄ is O, S,N—R₁, or CR₂: Z₅, Z₆, Z₇, Z₈ are independently N or CR₂; Y₁, Y₂, Y₃, andY₄ are C; one of Z₂, Z₃, Z₅, Z₆, Z₇, or Z₈ is a carbon atom to which theremainder of the molecule is attached.

[0144] The preferred embodiments of formula 3-A are:

[0145] 39. Z₁ is O, S, or N—R₁; Z₂ is N, or CR₂; Z₃ is CR₂; Z₅, Z₆, andZ₇ are independently N or CR₂; Z₄ and Z₈ are independently O, S, orN—R₁; Y₁, Y₂, Y₃, and Y₄ are C and one of Z₂, Z₅, Z₆, or Z₇ is a carbonatom to which the remainder of the molecule is attached.

[0146] 40. Z₃ is O, S, or N—R₁; Z₂ is N, CR₂; Z₁ is CR₂; Z₅, Z₆, and Z₇are independently N or CR₂; Z₄ and Z₈ are independently O, S, or N—R₁;Y₁, Y₂, Y₃, and Y₄ are C and one of Z₂, Z₅, Z₆, or Z₇ is a carbon atomto which the remainder of the molecule is attached.

[0147] The preferred embodiments of formula 3-B are:

[0148] 41. Z₁ is O, S, or N—R₁; Z₂ is N or CR₂; Z₃ is CR₂; Z₄, Z₅, Z₆,Z₇, and Z₈ are independently N or CR₂; Y₁, Y₂, Y₃, and Y₄ are C; and oneof Z₂, Z₅, Z₆, Z₇ is a carbon atom to which the remainder of themolecule is attached.

[0149] 42. Z₁ is N or CR₂; Z₂ is CR₂; Z₃ is O, S, N—R₁ or CR₂; Z₇ is CR₂or N; Z₆, and Z₈ are independently N or CR₂; Z and Z₅ are CR₂ or N; Y₁,Y₂, and Y₃ are C; Y₄ is N and one of Z₂, Z₄, Z₅, Z₆ is a carbon atom towhich the remainder of the molecule is attached.

[0150] 43. Z₁ is N, or CR₂; Z₂ is CR₂; Z₃ is O, S, N—R₁ or CR₂; Z₆ isCR₂ or N; Z₇, and Z₈ are independently N or CR₂; Z₄ and Z₅ areindependently CR₂ or N; Y₁, Y₂, Y₃ are C; Y₄ is N and one of Z₂, Z₄, Z₅,Z₆ is a carbon atom to which the remainder of the molecule is attached.

[0151] 44. Z₁ is O, S, or N—R₁; Z₂ is N, or CR₂; Z₃ is CR₂; Z₆, Z₇, andZ₈ are N; Z₄ and Z₅ are independently CR₂ or N; Y₁, Y₂, Y₄ are C; Y₃ isN and one of Z₂, or Z₃ is a carbon atom to which the remainder of themolecule is attached.

[0152] 45. Z₁ is N or CR₂; Z₂ is CR₂; Z₃ is O, S, N—R₁ or CR₂; Z₆, Z₇,and Z₈ are N; Z₄, and Z₅ are independently CR₂ or N; Y₁, Y₂, Y₄ are C;Y₃ is N and one of Z₁, Z₂ is a carbon atom to which the remainder of themolecule is attached.

[0153] 46. Z₁ is N or CR₂; Z₂ is CR₂; Z₃ is O, S, N—R₁ or CR₂; Z₆, Z₇,and Z₈ are N; Z₄ and Z₅ are independently CR₂ or N; Y₁, Y₂, Y₄ are C; Y₃is N and one of Z₁, Z₂, is a carbon atom to which the remainder of themolecule is attached.

[0154] 47. Z₁ is N; Z₂, Z₃, Z₄ and Z₅ are independently CR₂; Z₆, Z₇, andZ₈ are independently O, S, N, N—R₁ or CR₂; Y₂, Y₃, and Y₄ are C; Y₁ isN; one of Z₂, Z₃, Z₆, Z₆, Z₇, Z₈ is a carbon atom to which the remainderof the molecule is attached.

[0155] 48. Z₃ is N; Z₂ and Z₁ are independently CR₂; Z₄, and Z₅ areindependently CR₂; Z₆, Z₇, Z₈ are independently O, S, N,N—R₁ or CR₂; Y₂,Y₃, and Y₁ are C; Y₄ is N; one of Z₂, Z₁, Z₆, Z₆, Z₇, Z₈ is a carbonatom to which the remainder of the molecule is attached.

[0156] 49. Z₁ is N, or CR₂; Z₂ is CR₂; Z₃ is O, S, or N—R₁; Z₄ and Z₅are independently CR₂; Z₆, Z₇, Z₈ are independently O, S, N,N—R₁, orCR₂; Y₁, Y₂, Y₃, and Y₄ are C; one of Z₁, Z₂, Z₃, Z₆, Z₇, Z₈ is a carbonatom to which the remainder of the molecule is attached.

[0157] The Preferred embodiments of formula 4-A

[0158] 50. Z₁ and Z₃ are independently O, S, N—R₁, N, or CR₂; Z₂ is CR₂;Z₄, Z₅, Z₆, Z₇, Z₈, Z₉, are independently CR₂; Y₁, Y₂, Y₃, Y₄, are C.

[0159] 51. Z₁ and Z₃ are independently O, S, N—R₁, N, or CR₂; Z₂ is CR₂;Z₄, and Z₉ are independently CR₂, or N; Z₅, Z₆, Z₇, Z₈ are independentlyCR₂; Y₁, Y₂, Y₃, Y₄, are C; One of Z₁, Z₂, Z₃, Z₅, Z₆, Z₇, Z₈ is acarbon atom to which the remainder of the molecule is attached.

[0160] 52. Z₁ is S, O, or N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ areindependently CR₂; Z₉ is N; Y₁, Y₂, Y₃, Y₄, are C.

[0161] 53. Z₁, and Z₃ are independently O, S, N—R₁, N, or CR₂; Z₄, andZ₉, are independently N or CR₂; Z₅, Z₆, Z₇, Z₈ are independently CR₂ orN; Y₁, Y₂, Y₃, Y₄, are C; Z₂ is the carbon to which the remainder of themolecule is attached.

[0162] 54. Z₁ is N; Z₂, Z₃, and Z₄ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N or CR₂; Z₉ is CR₂ or N; Y₁ is N; Y₂, Y₃, and Y₄, areC; Z₂ or Z₃ is the carbon to which the remainder of the molecule isattached.

[0163] 55. Z₃ is N; Z₁, Z₂, and Z₄ are independently CR₂; Z₅, Z₆, Z₇,and Z₈ are independently CR₂, or N; Z₉ is CR₂, or N; Y₄ is N; Y₁, Y₂,and Y₃ are C.

[0164] The Preferred embodiments of formula 4-B

[0165] 56. Z₁ is N; Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈, and Z₉ are independentlyCR₂; Y₁ is N; Y₂, Y₃, and Y₄ are C; one of Z₂, Z₃, Z₆, Z₇, Z₈, Z₉ is thecarbon atom to which the remainder of the molecule is attached.

[0166] 57. Z₃ is N; Z₁, Z₂, and Z₄ are independently CR₂; Z₅, Z₆, Z₇,Z₈, and Z₉ are independently CR₂ or N; Y₁, Y₃, Y₄ are C; Y₂ is N.

[0167] 58. Z₁ is O, S, or N—R₁; Z₂, Z₃, and Z₄ are independently CR₂; Z₅is CR₂ or N; Z₆, Z₇, Z₈, and Z₉ are independently CR₂, or N; one of Z₆,Z₇, Z₈, Z₉ is a carbon atom to which the remainder of the molecule isattached.

[0168] 59. Z₁ and Z₃ are independently O, S, N—R₁, N, or CR₂; Z₄ is CR₂or N; Z₅ is CR₂; Z₆, Z₇, Z₈, and Z₉ are independently CR₂, or N; Y₁, andY₂ are independently C or N; Y₃ and Y₄ are C.

[0169] The Preferred embodiments of formula 4-C

[0170] 60. Z₁ and Z₂ are independently N or CR₂; Z₃, Z₄, Z₁, Z₆, Z₇, andZ₈ are independently CR₂; Y₁ is C.

[0171] 61. Z₁, and Z₂ are independently CR₂; Z₃, Z₄, Z₅, Z₆, Z₇, and Z₈are independently N or CR₂; Y₁ is C.

[0172] 62. Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, and Z₈ are independently N orCR₂; Y₁ is C.

[0173] The Preferred embodiments of formula 5-A

[0174] 63. Z₁ is O, S, or N—R₁; Z₂, and Z₃ are independently CR₂; Z₄ isO, S, N—R₁, or CR₂; Y₁, and Y₂ are C; Y₄, and Y₃ are independently C, orN; W₁, W₂, W₃ are independently CR₄R₄; t=1 or 2.

[0175] 64. Z₁ is O, S, or N—R₁; Z₂ and Z₁ are independently CR₂; Z₄ isO, S, N—R₁, or CR₂; Y₁, and Y₂ are C; Y₄, and Y₃ are independently C, orN; W₁, and W₃ are independently CR₄R₄; t=1 to 2; W₂ is O, S(O)r (r=0-2),N—R₁ or CR₄R₄.

[0176] 65. Z₃ is N; Z₂ is CR₂; Z₁ is CR₂, or N; Z₄ is O, S, N—R₁, W₁,W₂, and W₃ are independently CR₄R₄; t=1 to 3; Y₁, Y₃, and Y₄ are C; Y₂is N; one of Z₁, Z₂ or Z₄ is the carbon atom to which the remainder ofthe molecule is attached.

[0177] 66. Z₁ is N; Z₂ is CR₂; Z₃ is CR₂, or N; Z₄ is O, S, or N—R₁; W₁,W₂, and W₃ are independently CR₄R₄; t=1 to 3; Y₂, Y₃, and Y₄ are C; Y₁is N; one of Z₂, Z₃, Z₄ is the carbon atom to which the remainder of themolecule is attached.

[0178] 67. Z₃ is N; Z₂ is CR₂; Z₁ is CR₂, or N; Z₄ is O, S, or N—R₁; Y₁,Y₃, and Y₄ are C; Y₂ is N; W₁, W₂, and W₃ are independently CR₄R₄, OS(O)r (r=0-2), or N—R₁ with the proviso that no S—S, S—O or O—O bondformation can occur to form a saturated ring; t=1 to 3; one of Z₁, Z₂ orZ₄ is the carbon atom to which the remainder of the molecule isattached.

[0179] 68. Z₁ is N; Z₂ is CR₂; Z₃ is CR₂, or N; Z₄ is O, S, or N—R₁; Y₂,Y₃, and Y₄ are C; Y₁ is N; W₁, W₂, and W₃ are independently CR₄R₄, O,S═(O)r (r=0-2); or N—R₁, with the proviso that no S—S, S═O or O—O bondformation can occur to form a saturated ring; t=1-3; one of Z₂, Z₃, Z₄is a carbon atom to which the remainder of the molecule is attached.

[0180] 69. Z₁ is CR₂; Z₂ is the carbon atom to which the remainder ofthe molecule is attached; Z₃ is N; Z₄ is O, S, or N—R₁; Y₁ is C; Y₂ isN; Y₃, and Y₄ are C; W₁, W₂, and W₃ are independently CR₄R₄, O, S═(O)r(r=0-2), or N—R₁ with the proviso that no S—S, S═O or O—O bond formationcan occur to form a saturated ring; t=1 to 3.

[0181] 70. Z₁ is the carbon atom to which the remainder of the moleculeis attached; Z₂ is CR₂; Z₃ is N; Z₄ is O, S, N—R₁; Y₁ is C; Y₂ is N; Y₃,and Y₄ are C; W₁, W₂, and W₃ are independently CR₄R₄, O, S═(O)r (r=0-2),or N—R₁ with the proviso that no S—S, S═O or O—O bond formation canoccur to form a saturated ring; t=1-3.

[0182] 71. Z₁, Z₂, and Z₃ are independently CR₂, or N; Z₄ is CR₂; Y₁, Y₂are C; Y₃, Y₄ are N; W₁, W₂, and W₃ are independently CR₄R₄, O, S═(O)r(r=0-2), or N—R₁ with the proviso that no S—S, S—O or O—O bond formationcan occur to form a saturated ring; t=1-3.

[0183] The Preferred embodiments of formula 5-B

[0184] 72. Z₁, Z₂, Z₃, Z₄ are independently CR₂; Y₁, Y₂ are N; W₁, W₂are independently O, S, N—R₁, or CR₄R₄; t=1-2.

[0185] 73. Z₁, Z₂ are independently N, or CR₂; Z₃ is CR₂; Z₄ is O, S, orN—R₁; W₁, and W₂ are independently O, S, N—R₁, CR₄R₄; t=1-2.

[0186] The preferred embodiments of formula 6-A are:

[0187] 74. Z₁ is O, S, N—R₁; Z₂, Z₃, Z₄, Z₅ are independently CR₂; W₁,W₂, W₃ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; Y₁, Y₂are C; t=1-3; one of Z₂, Z₃ is the carbon atom to which the remainder ofthe molecule is attached.

[0188] 75. Z₁ is O, S, or N—R₁; Z₃ is N, O, or S; Z₂, Z₄, Z₅ areindependently CR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; Y₁, and Y₂ are C; t=1-3; Z₂ is the carbon atom towhich the remainder of the molecule is attached.

[0189] 76. Z₁ is CR₂; Z₃ is N; Z₂, Z, and Z₅ are independently CR₂; W₁,W₂, and W₃ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; Y₁ isN; Y₂ is C; t=1-3; Z₁, or Z₂ is the carbon atom to which the remainderof the molecule is attached.

[0190] 77. Z₁ is N; Z₂, Z₃, Z₄, Z₅ are independently CR₂; W₁, W₂, W₃ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; Y₁ is C; Y₂ is N;t=1-3; Z₂, or Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0191] 78. Z₁ is O, S, or N—R₁; Z₂ is N, O, or S; Z₃, Z₄, and Z₅ areindependently CR₂; W₁, W₂, and W₃ are independently N—R₁, O, S═(O),(r=0-2), or CR₄R₄; Y₁, and Y₂ are C; t=1-3; one of Z₃ is a carbon atomto which the remainder of the molecule is attached.

[0192] 79. Z₁ is O, S, or N—R₁; Z₂, and Z₃ are independently CR₂; Z₄,and Z₅ are independently CR₂, or N; W₁, W₂, and W₃ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; Y₁, Y₂ are C; t=1-3; Z₂ or Z₃ isthe carbon atom to which the remainder of the molecule is attached.

[0193] 80. Z₁ is O, S, or N—R₁; Z₃ is N, O, or S; Z₂ is CR₂; Z₄, Z₅ areindependently CR₂, or N; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; Y₁, Y₂ are C; t=1-3; Z₂ is the carbon atom to whichthe remainder of the molecule is attached.

[0194] 81. Z₁ is CR₂; Z₃ is N; Z₂ is CR₂; Z₁, Z₅ are independently N, orCR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄;Y₁ is N; Y₂ is C; t=1-3; Z₁ or Z₂ is the carbon atom to which theremainder of the molecule is attached.

[0195] 82. Z₁ is N; Z₂, and Z₃ are independently CR₂; Z₄, Z₅ areindependently N or CR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; Y₁ is C; Y₂ is N; t=1-3; Z₂ or Z₃ is the carbon atomto which the remainder of the molecule is attached.

[0196] 83. Z₁ is O, S, or N—R₁; Z₂ is N, O, or S; Z₃ is CR₂; Z₄, and Z₅are independently N, or CR₂; W₁, W₂, W₃ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; Y₁, Y₂ are C; t=1-3; Z₃ is the carbon atomto which the remainder of the molecule is attached.

[0197] The preferred embodiments of formula 6-B are:

[0198] 84. Z₁ is O, S, or N—R₁; Z₂, Z₃, Z₄, and Z₅ are independentlyCR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄;Y₁, Y₂, Y₃, and Y₄ are C; t=1-3; Z₂ or Z₃ is the carbon atom to whichthe remainder of the molecule is attached.

[0199] 85. Z₁ is O, S, or N—R₁; Z₃ is N, O, or S; Z₂, Z₄, Z₅ areindependently CR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; Y₁, Y₂, Y₃, Y₄ are C; t=1-3; Z₂ is the carbon atom towhich the remainder of the molecule is attached.

[0200] 86. Z₁ is CR₂; Z₃ is N; Z₂, Z₄, and Z₅ are independently CR₂; W₁,W₂, W₃ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; Y₃ is N;Y₁, Y₂, Y₄ are C; t=1-3; Z₁, or Z₂ is the carbon atom to which theremainder of the molecule is attached.

[0201] 87. Z₁ is N; Z₂, Z₃, Z₄, Z₅ are independently CR₂; W₁, W₂, W₃ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; Y₁, Y₂, Y₃ are C; Y₄is N; t=1-3; Z₂ or Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0202] 88. Z₁ is O, S, or N—R₁; Z₂ is N, O, or S; Z₃, 4, and Z₅ areindependently CR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; Y₁, Y₂, Y₃, and Y₄ are C; t=1-3; Z₃ is the carbonatom to which the remainder of the molecule is attached.

[0203] 89. Z₁ is O, S, or N—R₁; Z₂, and Z₃ are independently CR₂; Z₄,and Z₅ are independently CR₂, or N; W₁, W₂, W₃ are independently N—R₁,O, S═(O)_(r) (r=0-2), or CR₄R₄; Y₁, Y₂, Y₃, Y₄ are C; t=1-3; Z₂ or Z₃ isthe carbon atom to which the remainder of the molecule is attached.

[0204] 90. Z₁ is O, S, or N—R₁; Z₃ is N, O, or S; Z₂ is CR₂; Z₄, and Z₅are independently CR₂ or N; W₁, W₂, W₃ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; Y₁, Y₂, Y₃, Y₄ are C; t=1-3; Z₂ is thecarbon atom to which the remainder of the molecule is attached.

[0205] 91. Z₁ is CR₂; Z₃ is N; Z₂ is CR₂; Z₄, and Z₅ are independentlyN, CR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r) (r=0-2), orCR₄R₄; Y₃ is N; Y₁, Y₂, Y₄ are C; t=1-3; Z₁ or Z₂ is the carbon atom towhich the remainder of the molecule is attached.

[0206] 92. Z₁ is N; Z₂, Z₃ are independently CR₂; Z, Z₅ areindependently N, or CR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; Y₁, Y₂, Y₃ are C; Y₄ is N; t=1-3; Z₂, or Z₃ is thecarbon atom to which the remainder of the molecule is attached.

[0207] 93. Z₁ is O, S, or N—R₁; Z₂ is N, O, or S; Z₃ is CR₂; Z₄, Z₅ areindependently N, or CR₂; W₁, W₂, W₃ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; Y₁, Y₂, Y₃, Y₄ are C; t=1-3; Z₃ is the carbon atom towhich the remainder of the molecule is attached.

[0208] The preferred embodiments of formula 6-C are:

[0209] 94. Z₁, Z₃, Z₄, and Z₅ are independently N or CR₂; Z₂ is O, S, orN—R₁; Y₁, Y₂ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2),CR₄R₄; t=1-2.

[0210] 95. Z₁, Z₃, Z₄, Z₅ are independently CR₂; Z₂ is O, S, or N—R₁;Y₁, Y₂ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), orCR₄R₄; t=1-2.

[0211] 96. Z₁, Z₃, Z₅ are independently CR₂; Z₂ is O, S, N—R₁; Z is N;Y₁ Y₂ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), orCR₄R₄; t=1-2.

[0212] 97. Z₁, Z₂, Z₃ Z₁, and Z₅ are independently CR₂; Y₁ is C; Y₂ isN; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2.

[0213] 98. Z₁, Z₂, Z₃, Z₅ are independently CR₂; Z₄ is N; Y₁ is C; Y₂ isN; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2.

[0214] The preferred embodiments of formula 7-A are:

[0215] 99. Z₃, Z₆ are independently O, S, or N—R₁; Z₁, Z₂, Z₄, Z₅ areindependently CR₂; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2),or CR₄R₄; t=1-2.

[0216] 100. Z₃, Z₆ are independently O, S, or N—R₁; Z₁, Z₄ are N; Z₂, Z₅are independently CR₂; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; t=1-2; Z₂ or Z₅ is the carbon atom to which theremainder of the molecule is attached.

[0217] 101. Z₁, Z₄ are independently O, S, or N—R₁; Z₂, Z₃, Z₅, Z₆ areindependently CR₂; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2),or CR₄R₄; t=1-2.

[0218] 102. Z₁, Z₄ are independently O, S, or N—R₁; Z₃, Z₆ are N; Z₂, Z₅are independently CR₂; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; t=1-2; Z₂ or Z₅ is the carbon atom to which theremainder of the molecule is attached.

[0219] 103. Z₂, Z₅ are independently O, S, or N—R₁; Z₁, Z₃, Z₄, Z₆ areindependently CR₂; W₁, W₂ are independently N—R₁, O, S═(O), (r=0-2), orCR₄R₄; t=1-2.

[0220] 104. Z₂, Z₅ are independently O, S, N—R₁; Z₁, Z₃. Z₄, Z₆ areindependently CR₂, N, S; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=1-2; One of Z₁, Z₃, Z₄, Z₆ is the carbon atom to whichthe remainder of the molecule is attached.

[0221] 105. Z₁ is CR₂, N; Z₂ is CR₂; Z₃ is N; Z₄, Z₅ are independentlyCR₂; Z₆ is N; Y₁, Y₃ are independently CR₂; Y₂, Y₄ are N; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₄, Z₅ is the carbon atom to which the remainder of the molecule isattached.

[0222] 106. Z₁ is CR₂, or N; Z₂ is CR₂; Z₃ is O, S, N—R₁; Z₄, Z₅ areindependently CR₂; Z₆ is N; Y₁, Y₄, Y₃ are independently CR₂; Y₂ is N;W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=1-2; Oneof Z₁, Z₂, Z₄, Z₅ is the carbon atom to which the remainder of themolecule is attached.

[0223] 107. Z₁ is CR₂, or N; Z₂ is CR₂; Z₃ is N; Z₄, Z₅, Z₆ areindependently N, or CR₂; Y₁, and Y₃ are N; Y₂, Y₄ are independently CR₂;W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2;One of Z₁, Z₂, Z₄, Z₅, Z₆ is the carbon atom to which the remainder ofthe molecule is attached.

[0224] The preferred embodiments of formula 7-B are:

[0225] 108. Z₁, Z₂, Z₄, Z₅, Z₆ are independently CR₂; Z₃ is O, S, orN—R₁; Y₁, Y₂, Y₄ are C; Y₃ is N; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2.

[0226] 109. Z₁, Z₂, Z₄, Z₅, Z₆ are independently CR₂ or N; Z₃ is O, S,or N—R₁; Y₁, Y₂, Y₄ are C; Y₃ is N; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₄, Z₅, Z₆ is thecarbon atom to which the remainder of the molecule is attached.

[0227] 110. Z₁, Z₂, Z₃, Z₅, Z₆ are independently CR₂; Z is O, S, orN—R₁; Y₁, Y₂, Y₃ are C; Y₄ is N; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₃, Z₅, Z₆ is thecarbon atom to which the remainder of the molecule is attached.

[0228] 111. Z₁, Z₂, Z₃, Z₅, Z₆ are independently CR₂ or N; Z₄ is O, S,or N—R₁; Y₁, Y₂, Y₃ are C; Y₄ is N; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₃, Z₅, Z₆ is thecarbon atom to which the remainder of the molecule is attached.

[0229] 112. Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₃ are N;Y₂, Y₄ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), orCR₄R₄; t=1-2; One of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ is the carbon atom to whichthe remainder of the molecule is attached.

[0230] 113. Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ are independently CR₂ or N; Y₁, Y₃are N; Y₂, Y₄ are C; W₁, W₂ are independently N—R₁, O, S═(O), (r=0-2),or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ is the carbon atom towhich the remainder of the molecule is attached.

[0231] 114. Z₁, Z₃, Z₄, Z₅, Z₆ are independently CR₂; Z₂ is O, S, orN—R₁; Y₁, Y₂, Y₄ is C; Y₃ is N; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₃, Z₄, Z₅, Z₆ is thecarbon atom to which the remainder of the molecule is attached.

[0232] 115. Z₁, Z₃, Z₄, Z₅, Z₆ are independently CR₂, or N; Z₂ is O, S,or N—R₁; Y₁, Y₂, Y₄ are C; Y₃═N; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₃, Z₄, Z₅, Z₆ is thecarbon atom to which the remainder of the molecule is attached.

[0233] 116. Z₁, Z₂, Z₄, Z₆ are independently CR₂; Z₃, Z₅ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₄, Z₆ is the carbon atom to which the remainder of the molecule isattached.

[0234] 117. Z₁, Z₂, Z₄, Z₆ are independently CR₂, or N; Z₃, Z₅ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁ Z₂,Z₄, Z₆ is the carbon atom to which the remainder of the molecule isattached.

[0235] 118. Z₁, Z₂, Z₄, Z₅ are independently CR₂; Z₃, Z₆ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₄, Z₅ is the carbon atom to which the remainder of the molecule isattached.

[0236] 119. Z₁, Z₂, Z₄, Z₅ are independently CR₂, or N; Z₃, Z₆ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₄, Z₅ is the carbon atom to which the remainder of the molecule isattached.

[0237] 120. Z₁, Z₂, Z₅, Z₆ are independently CR₂; Z₃, Z₄ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₅, Z₆ is the carbon atom to which the remainder of the molecule isattached.

[0238] 121. Z₁, Z₂, Z₅, Z₆ are independently CR₂ or N; Z₃, Z₄ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₅, Z₆ is the carbon atom to which the remainder of the molecule isattached.

[0239] 122. Z₁, Z₂, Z₄, Z₅ are independently CR₂; Z₃, Z₆ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₅, Z₆ is the carbon atom to which the remainder of the molecule isattached.

[0240] 123. Z₁, Z₂, Z₄, Z₅ are independently CR₂, or N; Z₃, Z₆ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₅, Z₆ is the carbon atom to which the remainder of the molecule isattached.

[0241] 124. Z₁, Z₂, Z₃, 14, Z₆ are independently CR₂; Z₅ is O, S, orN—R₁; Y₁ is N; Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₃, Z₄, Z₆ is thecarbon atom to which the remainder of the molecule is attached.

[0242] 125. Z₁, Z₂, Z₃, Z₄, Z₆ are independently CR₂, or N; Z₅ is O, S,or N—R₁; Y₁ is N; Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₃, Z₄, Z₆ is thecarbon atom to which the remainder of the molecule is attached.

[0243] 126. Z₁, Z₃, Z₄, Z₆ are independently CR₂; Z₂, Z₅ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₃, Z₄, Z₆ is the carbon atom to which the remainder of the molecule isattached.

[0244] 127. Z₁, Z₃, Z₄, Z₆ are independently CR₂ or N; Z₂, Z₅ areindependently O, S, or N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₃, Z, Z₆ is the carbon atom to which the remainder of the molecule isattached.

[0245] The preferred embodiments of formula 8-A are:

[0246] 128. Z₁ is O, S, or N—R₁; Z₂, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂; Z₃ is CR₂, or N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂, Z₃, Z₄, Z₆ isthe carbon atom to which the remainder of the molecule is attached.

[0247] 129. Z₁ is O, S, or N—R₁; Z₂, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂; Z₃ is CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0248] 130. Z₁ is O, S, or N—R₁; Z₂, 4, Z₅, Z₆, Z₇ are independentlyCR₂; Z₃ is N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂, Z₄, Z₅, Z₆, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0249] 131. Z₁ is O, S, or N—R₁; Z₃, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂; Z₂ is CR₂, or N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂, Z₃, Z₄, Z₅, Z₆,Z₇ is the carbon atom to which the remainder of the molecule isattached.

[0250] 132. Z₁ is O, S, or N—R₁; Z₃, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂; Z₂ is N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S=(°)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₃, Z₄, Z₅, Z₆, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0251] 133. Z₁ is O, S, or N—R₁; Z₃, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂; Z₂ is CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0252] 134. Z₁ is O, S, or N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ areindependently N or CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂, Z₃, 14, Z₅, Z₆,Z₇ is the carbon atom to which the remainder of the molecule isattached.

[0253] 135. Z₁ is O, S, or N—R₁; Z₂ is CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N or CR₂; Z₃ is CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂,Z₃, Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of themolecule is attached.

[0254] 136. Z₁ is O, S, or N—R₁; Z₂ is CR₂; Z₄, Z₅, Z₆, and Z₇ areindependently N or CR₂; Z₃ is N; Y₁, Y₂, Y₃, Y₄ are C; W₁, and W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0255] 137. Z₁ is O, S, or N—R₁; Z₄, Z₅, Z₆, and Z₇ are independently Nor CR₂; Z₂ and Z₃ are independently CR₂ or N; Y₁, Y₂, Y₃, Y₄ are C; W₁and W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2;One of Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainderof the molecule is attached.

[0256] 138. Z₁ is O, S, or N—R₁; Z₃ is CR₂; Z₄, Z₅, Z₆, and Z₇ areindependently N or CR₂; Z₂ is N; Y₁, Y₂, Y₃, and Y₄ are C; W₁ and W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₃,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0257] 139. Z₁ is O, S, N—R₁; Z₄, Z₅, Z₆, and Z₇ are independently N orCR₂; Z₂ and Z₃ are independently CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁ and W₂are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One ofZ₂, Z₃, Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of themolecule is attached.

[0258] 140. Z₃ is O, S, or N—R₁; Z₂, Z₄, Z₅, Z₆, and Z₇ areindependently CR₂; Z₁ is CR₂ or N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O), (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0259] 141. Z₃ is O, S, or N—R₁; Z₁, Z₂, Z₄, Z₅, Z₆, Z₇ areindependently CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁,O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, 4, Z₅, Z₆, Z₇ isthe carbon atom to which the remainder of the molecule is attached.

[0260] 142. Z₃ is O, S, or N—R₁; Z₂, Z₄, Z₅, Z₆, and Z₇ areindependently CR₂; Z₁ is N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of themolecule is attached.

[0261] 143. Z₃ is O, S, or N—R₁; Z₁, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂; Z₂ is CR₂ or N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₄, Z₅, Z₆,Z₇ is the carbon atom to which the remainder of the molecule isattached.

[0262] 144. Z₃ is O, S, or N—R₁; Z₁, Z₄, Z₅, Z₆, Z₇ are independentlyCR₂; Z₂ is N; Y₁, Y₂, Y₃, Y₄ are C; W, and W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₄, Z₅, Z₆, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0263] 145. Z₃ is O, S, or N—R₁; Z₁, Z₂, Z₄, Z₅, Z₆, Z₇ areindependently CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁ and W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₄, Z₅, Z₆,Z₇ is the carbon atom to which the remainder of the molecule isattached.

[0264] 146. Z₁ is O, S, or N—R₁; Z₂, Z₄, Z₅, Z₆, Z₇ are independently Nor CR₂; Z₁ is CR₂, or N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=1-2; One of Z₁, Z_(2, 14), Z₅, Z₆,Z₇ is the carbon atom to which the remainder of the molecule isattached.

[0265] 147. Z₃ is O, S, or N—R₁; Z₂ is CR₂; Z₄, Z_(5, 1), Z₇ areindependently N or CR₂; Z₁ is CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁ and W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₁,Z₂, Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of themolecule is attached.

[0266] 148. Z₃ is O, S, or N—R₁; Z₂ is CR₂; Z₄, Z₅, Z₆, and Z₇ areindependently N or CR₂; Z₁ is N; Y₁, Y₂, Y₃, Y₄ are C; W₁ and W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0267] 149. Z₃ is O, S, or N—R₁; Z₄, Z₅, Z₆, and Z₇ are independently Nor CR₂; Z₂ and Z₁ are independently CR₂ or N; Y₁, Y₂, Y₃, Y₄ are C; W₁and W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2;One of Z₇, Z₂, Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainderof the molecule is attached.

[0268] 150. Z₃ is O, S, N—R₁; Z₇ is CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N or CR₂; Z₂ is N; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=1-2; One of Z₁, Z₄,Z₅, Z₆, and Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0269] 151. Z₃ is O, S, N—R₁; Z₄, Z₅, Z₆, and Z₇ are independently N orCR₂; Z₁ and Z₂ are independently CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁ and W₂are independently N—R₁, O, S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One ofZ₇, Z₂, Z₄, Z₆, and Z₇ is the carbon atom to which the remainder of themolecule is attached.

[0270] 152. Z₇, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are independently CR₂; Y₄ isN; Y₁, Y₂, Y₃ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₃, Z₄, Z₆, Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0271] 153. Z₁ is N; Z₂, Z_(3, 4), Z₅, Z₆, and Z₇ are independently CR₂;Y₄ is N; Y₁, Y₂, Y₃ are C; W₁ and W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), or CR₄R₄; t=1-2; One of Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ isthe carbon atom to which the remainder of the molecule is attached.

[0272] 154. Z₂ is N; Z₁, Z₃, Z₄, Z₅, Z₆, Z₇ are independently CR₂; Y₄ isN; Y₁, Y₂, Y₃ are C; W₁ and W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=1-2; One of Z₁, Z₃, Z₄, Z₅, Z₆, and Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0273] 155. Z₃ is N; Z₁, Z₂, Z₄, Z₅, Z₆, and Z₇ are independently CR₂;Y₄ is N; Y₁, Y₂, Y₃ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), or CR₄R₄; t=1-2; One of Z₁, Z₂, Z₄, Z₅, Z₆, and Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0274] 156. Z₁ and Z₂ are N; Z₃, Z₄, Z₅, Z₆, Z₇ are independently CR₂;Y₄ is N; Y₁, Y₂, Y₃ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=1-2; One of Z₃, Z₄, Z₅, Z₆, Z₇ is the carbon atom towhich the remainder of the molecule is attached.

[0275] 157. Z₁, Z₃ are N; Z₂, Z₄, Z₅, Z₆, Z₇ are independently CR₂; Y₄is N; Y₁, Y₂, Y₃ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=1-2; One of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0276] 158. Z₁, Z₂, Z₃ are N; Z₄, Z₅, Z₆, Z₇ are independently CR₂; Y₄is N; Y₁, Y₂, Y₃ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=1-2; One of Z₄, Z₅, Z₆, Z₇ is the carbon atom to whichthe remainder of the molecule is attached.

[0277] 159. Z₁, Z₂, Z₃ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₁, Y₂, Y₃ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=1-2; One of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of themolecule is attached.

[0278] 160. Z₁ is N; Z₂, Z₃ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₁, Y₂ Y₃ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=1-2; One of Z₂, Z₃, Z₄, Z₅, Z₆, Z₇is the carbon atom to which the remainder of the molecule is attached.

[0279] 161. Z₂ is N; Z₁, Z₃ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₁, Y₂. Y₃ are C; W₁, W₂, areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=1-2; One of Z₁, Z₃,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0280] 162. Z₃ is N; Z₁, Z₂ are independently CR₂; 4, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₁, Y₂. Y₃ are C; W₁, W₂ areindependently N—R₁, O, S═(O), (r=0-2), CR₄R₄; t=1-2; One of Z₁, Z₂, Z,Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the molecule isattached.

[0281] 163. Z₁, Z₂ are N; Z₃ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₁, Y₂, Y₃ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=1-2; One of Z₃, Z₄,Z₅, Z₇ is the carbon atom to which the remainder of the molecule isattached.

[0282] 164. Z₁, Z₃ are N; Z₂ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₁, Y₂, Y₃ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=1-2; One of Z₁, Z₂,Z₃ Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of themolecule is attached.

[0283] 165. Z₁, Z₂, Z₃ are N; Z₄, Z₅, Z₆, Z₇ are independently N, CR₂;Y₄ is N; Y₁, Y₂, Y₃ are C; W₁, W₂ are independently N—R₁, O, S═(O),(r=0-2), CR₄R₄; t=1-2; One of Z₄, Z₅, Z₆, Z₇ is the carbon atom to whichthe remainder of the molecule is attached.

[0284] The preferred embodiments of formula 8-B are:

[0285] 166. Z₁ is O, S, N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ are independentlyN, CR₂; Y., Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0286] 167. Z₁ is O, S, N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ are CH₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r) (r=0-2),CR₄R₄; t=0-2; One of Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ is the carbon atom to whichthe remainder of the molecule is attached.

[0287] 168. Z₁ is O, S, N—R₁; Z₂ is N; Z₃, Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₃, Z₄, Z₅, Z₆, Z₇ isthe carbon atom to which the remainder of the molecule is attached.

[0288] 169. Z₁ is O, S, N—R₁; Z₂, Z₃ are N; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₄, Z₅, Z₆, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0289] 170. Z₁ is O, S, N—R₁; Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ are independentlyN, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₃ is N; Z₂, Z₄, Z₅, Z₆, Z₇ isthe carbon atom to which the remainder of the molecule is attached.

[0290] 171. Z₂ is O, S, N—R₁; Z₁, Z₃, Z₄, Z₅, Z₆, Z₇ are independentlyN, CR₂; Y₁, Y₂. Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₃, Z₄, Z₅, A, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0291] 172. Z₂ is O, S, N—R₁; Z₁, Z₃, Z₄, Z₅, Z, Z₇ are independentlyCR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₃, Z₄, Z₅, Z₆, Z₇ is the carbon atomto which the remainder of the molecule is attached.

[0292] 173. Z₂ is O, S, N—R₁; Z₁ is N; Z₃ is CR₂; Z, Z₅, Z₁, Z₇ areindependently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₃, Z₄, Z₅, Z₆, Z₇ isthe carbon atom to which the remainder of the molecule is attached.

[0293] 174. Z₂ is O, S, N—R₁; Z₁, Z₃ are N; Z₄, Z₅, Z₁, Z₇ areindependently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₄, Z₅, Z₁, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0294] 175. Z₃ is O, S, N—R₁; Z₁, Z₂, Z₄, Z₅, Z₆, Z₇ are independentlyN, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₂, Z₄, Z₅, Z, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0295] 176. Z₃ is O, S, N—R₁; Z₁, Z₂, 4, Z₅, Z, Z₇ are independentlyCR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₂, Z, Z₅, Z₆, Z₇ is the carbon atomto which the remainder of the molecule is attached.

[0296] 177. Z₃ is O, S, N—R₁; Z, is N; Z₂ is CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₂, Z₄, Z₅, Z₆, Z₇ isthe carbon atom to which the remainder of the molecule is attached.

[0297] 178. Z₃ is O, S, N—R₁; Z₁, Z₂ is N; Z, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independentlyN—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₄, Z₅, Z₆, Z₇ is thecarbon atom to which the remainder of the molecule is attached.

[0298] 179. Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ are independently N, CR₂; Y₁ isN; Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0299] 180. Z₁ is N; Z₂, Z₃ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₂, Z₃,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0300] 181. Z₁, Z₂ are N; Z₃ is CR₂; Z₄, Z₅, Z₆, Z₇ are independently N,CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₃, Z₄, Z₅, Z₆, Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0301] 182. Z₁, Z₂, Z₃ are N; Z₄, Z₅, Z₆, Z₇ are independently N, CR₂;Y₁ is N; Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; One of Z₄, Z₅, Z₆, Z₇ is the carbon atom to whichthe remainder of the molecule is attached.

[0302] 183. Z₂ is N; Z₁, Z₃ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₃,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0303] 184. Z₂ Z₃ are N; Z₁ is CR₂; Z₄, Z₅, Z₆, Z₇ are independently N,CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₄, Z₅, Z₆, Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0304] 185. Z₃ is N; Z₁, Z₂ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₁ is N; Y₂, Y₃, Y₄ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₂,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0305] 186. Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ are independently N, CR₂; Y₄ isN; Y₂, Y₃, Y₁ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0306] 187. Z₁ is N; Z₂, Z₃ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₂, Y₃, Y₁ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₂, Z₃,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0307] 188. Z₁, Z₂ are N; Z₃ is CR₂; Z₄, Z₅, Z₆, Z₇ are independently N,CR₂; Y₄ is N; Y₂, Y₃, Y₁ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₃, Z₄, Z₅, Z₆, Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0308] 189. Z₁, Z₂, Z₃ are N; Z₄, Z₅, Z₆, Z₇ are independently N, CR₂;Y₄ is N; Y₂, Y₃, Y₁ are C; W₁, W₂ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; One of Z₄, Z₅, Z₆, Z₇ is the carbon atom to whichthe remainder of the molecule is attached.

[0309] 190. Z₂ is N; Z₁, Z₃ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₂, Y₃, Y₁ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₃,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0310] 191. Z₂, Z₃ are N; Z₁ is CR₂; Z₄, Z₅, Z₆, Z₇ are independently N,CR₂; Y₄ is N; Y₂, Y₃, Y₁ are C; W₁, W₂ are independently N—R₁, O,S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₄, Z₅, Z₆, Z₇ is the carbonatom to which the remainder of the molecule is attached.

[0311] 192. Z₃ is N; Z₁, Z₂ are independently CR₂; Z₄, Z₅, Z₆, Z₇ areindependently N, CR₂; Y₄ is N; Y₂, Y₃, Y₁ are C; W₁, W₂ areindependently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄; t=0-2; One of Z₁, Z₂,Z₄, Z₅, Z₆, Z₇ is the carbon atom to which the remainder of the moleculeis attached.

[0312] The preferred embodiments of formula 9-A are:

[0313] 193. Z₁ is O, S, N—R₁; Z₂, Z₃ are independently CR₂; Y₁, Y₄ areC; Y₂, Y₃ are independently N, C, CH (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₂, Z₃ is the carbon atom to whichthe remainder of the molecule is attached.

[0314] 194. Z₁ is O, S, N—R₁; Z₂ is N; Z₃ is CR₂; Y₁, Y₄ are C; Y₂, Y₃are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0315] 195. Z₁ is O, S, N—R₁; Z₃ is N Z₂ is CR₂; Y₁, Y₄ are C; Y₂, Y₃are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₂ is the carbon atom to which the remainder of themolecule is attached.

[0316] 196. Z₂ is O, S, N—R₁; Z₁, Z₃ are independently CR₂; Y₁, Y₄ areC; Y₂, Y₃ are independently C, CH, N (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₂, Z₃ is the carbon atom to whichthe remainder of the molecule is attached.

[0317] 197. Z₂ is O, S, N—R₁; Z₁ is N; Z₃ is CR₂; Y₁, Y₄ are C; Y₂, Y₃are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0318] 198. Z₂ is O, S, N—R₁; Z₃ is N Z₁ is CR₂; Y₁, Y₄ are C; Y₂, Y₃are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₁ is the carbon atom to which the remainder of themolecule is attached.

[0319] 199. Z₃ is O, S, N—R₁; Z₁, Z₂ are independently CR₂; Y₁, Y₄ areC; Y₂, Y₃ are independently C, CH, N (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₁, Z₂ is the carbon atom to whichthe remainder of the molecule is attached.

[0320] 200. Z₃ is O, S, N—R₁; Z₁ is N; Z₂ is CR₂; Y₁, Y₄ are C; Y₂, Y₃are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₂ is the carbon atom to which the remainder of themolecule is attached.

[0321] 201. Z₃ is O, S, N—R₁; Z₁ is CH₂; Z₂ is N; Y₁, Y₄ are C; Y₂, Y₃are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₁ is the carbon atom to which the remainder of themolecule is attached.

[0322] 202. Z₁, Z₂, Z₃ are independently CR₂; Y₁ is N; Y₄ is C; Y₂, Y₃are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; One of Z₁, Z₂, Z₃ is the carbon atom to which theremainder of the molecule is attached.

[0323] 203. Z₁ is N; Z₂, Z₃ are independently CR₂; Y₁ is N; Y₄ is C; Y₂,Y₃ are independently C, CH. N (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₂, Z₃ is the carbon atom to whichthe remainder of the molecule is attached.

[0324] 204. Z₁, Z₂ is N; Z₃ is CR₂; Y₁ is N; Y₄ is C; Y₂, Y₃ areindependently C, CH, N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0325] 205. Z₁, Z₃ are N; Z₂ is CR₂; Y₁ is N; Y₄ is C; Y₂, Y₃ areindependently C, CH, N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₂ is the carbon atom to which the remainder of themolecule is attached.

[0326] 206. Z₁, Z₂, Z₃ are independently CR₂; Y₄ is N; Y₁ is C; Y₂, Y₃are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; One of Z₁, Z₂, Z₃ is the carbon atom to which theremainder of the molecule is attached.

[0327] 207. Z₁ is N; Z₂, Z₃ are independently CR₂; Y₄ is N; Y₁ is C; Y₂,Y₃ are independently C, CH. N (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₂, Z₃ is the carbon atom to whichthe remainder of the molecule is attached.

[0328] 208. Z₁, Z₂ are N; Z₃ is CR₂; Y₄ is N; Y₁ is C; Y₂, Y₃ areindependently C, CH, N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0329] 209. Z₁, Z₃ are N; Z₂ is CR₂; Y₄ is N; Y₁ is C; Y₂, Y₃ areindependently C, CH, N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₂ is the carbon atom to which the remainder of themolecule is attached.

[0330] The preferred embodiments of formula 9-B:

[0331] 210. Z₁ is O, S, N—R₁; Z₂, Z₃ are independently CR₂; Y₁, Y₂ areC; Y₃, Y₄ are independently N, C, CH (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₂, Z₃ is the carbon atom to whichthe remainder of the molecule is attached.

[0332] 211. Z₁ is O, S, N—R₁; Z₂ is N; Z₃ is CR₂; Y₁, Y₂ are C; Y₃, Y₄are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0333] 212. Z₁ is O, S, N—R₁; Z₃ is N Z₂ is CR₂; Y₁, Y₂ are C; Y₃, Y₄are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₂ is the carbon atom to which the remainder of themolecule is attached.

[0334] 213. Z₂ is O, S, N—R₁; Z₁, Z₃ are independently CR₂; Y₁, Y₂ areC; Y₃, Y₄ are independently C, CH, N (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₂, Z₃ is the carbon atom to whichthe remainder of the molecule is attached.

[0335] 214. Z₂ is O, S, N—R₁; Z₁ is N; Z₃ is CR₂; Y₁, Y₂ are C; Y₃, Y₄are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0336] 215. Z₂ is O, S, N—R₁; Z₃ is N Z, is CR₂; Y₁, Y₂ are C; Y₃, Y₄are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₁ is the carbon atom to which the remainder of themolecule is attached.

[0337] 216. Z₃ is O, S, N—R₁; Z₁, Z₂ are independently CR₂; Y₁, Y₂ areC; Y₃, Y₄ are independently C, CH, N (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₁, Z₂ is the carbon atom to whichthe remainder of the molecule is attached.

[0338] 217. Z₃ is O, S, N—R₁; Z₁ is N; Z₂ is CR₂; Y₁, Y₂ are C; Y₃, Y₄are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₂ is the carbon atom to which the remainder of themolecule is attached.

[0339] 218. Z₃ is O, S, N—R₁; Z₁ is CH₂; Z₂ is N; Y₁, Y₂ are C; Y₃, Y₄are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₁ is the carbon atom to which the remainder of themolecule is attached.

[0340] 219. Z₁, Z₂, Z₃ are independently CR₂; Y₁ is N; Y₂ is C; Y₃, Y₄are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; One of Z₁, Z₂, Z₃ is the carbon atom to which theremainder of the molecule is attached.

[0341] 220. Z₁ is N; Z₂, Z₃ are CR₂; Y₁ is N; Y₂ is C; Y₃, Y₄ areindependently C, CH. N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; One of Z₂, Z₃ is the carbon atom to which the remainder ofthe molecule is attached.

[0342] 221. Z₁, Z₂ are N; Z₃ is CR₂; Y₁ is N; Y₂ is C; Y₃, Y₄ areindependently C, CH, N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0343] 222. Z₁, Z₃ are N; Z₂ is CR₂; Y₁ is N; Y₂ is C; Y₃, Y₄ areindependently C, CH, N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₂ is the carbon atom to which the remainder of themolecule is attached.

[0344] 223. Z₁, Z₂, Z₃ are independently CR₂; Y₂ is N; Y₁ is C; Y₃, Y₄are independently C, CH, N (in between a double bond might be present);W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; One of Z₁, Z₂, Z₃ is the carbon atom to which theremainder of the molecule is attached.

[0345] 224. Z₁ is N; Z₂, Z₃ are independently CR₂; Y₂ is N; Y₁ is C; Y₃,Y₄ are independently C, CH. N (in between a double bond might bepresent); W₁, W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r)(r=0-2), CR₄R₄; t=0-2; u=1-3; One of Z₂, Z₃ is the carbon atom to whichthe remainder of the molecule is attached.

[0346] 225. Z₁, Z₂ are N; Z₃ is CR₂; Y₂ is N; Y₁ is C; Y₃, Y₄ areindependently C, CH, N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0347] 226. Z₁, Z₃ are N; Z₂ is CR₂; Y₂ is N; Y₁ is C; Y₃, Y₄ areindependently C, CH, N (in between a double bond might be present); W₁,W₂, W₃, W₄, W₅ are independently N—R₁, O, S═(O)_(r) (r=0-2), CR₄R₄;t=0-2; u=1-3; Z₂ is the carbon atom to which the remainder of themolecule is attached.

[0348] The preferred embodiments of formula 10-A:

[0349] 227. Z₁, Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ are independently CR₂; Z₅ isO, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉must be a carbon atom to which the remainder of the molecule isattached.

[0350] 228. Z₁ is N; Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ are independently CR₂;Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one of Z₂, Z₃, Z₄, Z₆, Z₇, Z₈,Z₉ must be a carbon atom to which the remainder of the molecule isattached.

[0351] 229. Z₁, Z₂ are N; Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ are independently CR₂;Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one of Z₃, Z₄, Z₆, Z₇, Z₈, Z₉must be a carbon atom to which the remainder of the molecule isattached.

[0352] 230. Z₁, Z₃ are N; Z₂, Z₄, Z₆, Z₇, Z₈, Z₉ are independently CR₂;Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one of Z₂, Z₄, Z₆, Z₇, Z₈, Z₉must be a carbon atom to which the remainder of the molecule isattached.

[0353] 231. Z₁, Z₄ are N; Z₃, Z₆, Z₇, Z₈, Z₉ are independently CR₂; Z₅is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one of Z₃, Z₆, Z₇Z₈, Z₉, must be acarbon atom to which the remainder of the molecule is attached.

[0354] 232. Z₁ is N; Z₂, Z₃, Z₄ are independently CR₂; Z₆, Z₇, Z₈, Z₉are independently N, CR₂; Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one ofZ₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainderof the molecule is attached.

[0355] 233. Z₁, Z₂ are N; Z₃, Z are independently CR₂; Z₆. Z₇, Z₈, Z₉are independently N, CR₂; Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one ofZ₃, Z₄, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainder ofthe molecule is attached.

[0356] 234. Z₁, Z₃ are N; Z₂, Z₄ are independently CR₂; Z₆, Z₇. Z₈, Z₉are independently N, CR₂; Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one ofZ₂, Z₄, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainder ofthe molecule is attached.

[0357] 235. Z₁, Z₄ are N; Z₂, Z₃ are independently CR₂; Z₆, Z₇, Z₈, Z₉are independently N, CR₂; Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one ofZ₂, Z₃, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainder ofthe molecule is attached.

[0358] 236. Z₂ is N; Z₁, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ are independently CR₂;Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₃, Z₄, Z₆, Z₇, Z₈,Z₉ must be a carbon atom to which the remainder of the molecule isattached.

[0359] 237. Z₂, Z₃ are N; Z₁, Z₄, Z₆, Z₇, Z₈, Z₉ are independently CR₂;Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₄, Z₆, Z₇, Z₈, Z₉must be a carbon atom to which the remainder of the molecule isattached.

[0360] 238. Z₂, Z₄ are N; Z₁, Z, Z₁, Z₇, Z₁, Z₁ are independently CR₂;Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one of Z₁, Z₃, Z₆, Z₇, Z₈, Z₉must be a carbon atom to which the remainder of the molecule isattached.

[0361] 239. Z₂ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₆, Z₇, Z₈, Z₉are independently N, CR₂; Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one ofZ₁, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainderof the molecule is attached.

[0362] 240. Z₂, Z₃ are N; Z₁, Z₄ are independently CR₂; Z₆, Z₇, Z₈, Z₉are independently N, CR₂; Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one ofZ₁, Z₄, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainder ofthe molecule is attached.

[0363] 241. Z₂, Z₄ are N; Z₁, Z₃ are independently CR₂; Z₆, Z₇, Z₈, Z₉are independently N, CR₂; Z₅ is O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; one ofZ₁, Z₃, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainder ofthe molecule is attached.

[0364] The preferred embodiments of formula 11-A:

[0365] 242. Z₁, Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ are independently CR₂; Z₅,Z₁₀ are independently O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁,Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainderof the molecule is attached.

[0366] 243. Z₁, Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ are independently N, CR₂; Z₅,Z₁₀ are independently O, S, N—R₁; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁,Z₂, Z, 14, Z₆, Z₇, Z₈, Z₉ must be a carbon atom to which the remainderof the molecule is attached.

[0367] The preferred embodiments of formula 11-B:

[0368] 244. Z₁, Z₂, Z₃, Z₄, Z₇, Z₈, Z₉, Z₁₀ are independently CR₂; Z₅,Z₆ are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁, Z₂,Z₃, Z₄, Z₇, Z₈, Z₉, Z₁₀ must be a carbon atom to which the remainder ofthe molecule is attached.

[0369] 245. 163. Z₁, Z₂, Z₃, Z₄ are independently CR₂, N; Z₅, Z₆, Z₇,Z₈, Z₉ Z₁₀ are independently CR₂; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁,Z₂, Z₃, Z₄, Z₇, Z₈, Z₉, Z₁₀ must be a carbon atom to which the remainderof the molecule is attached.

[0370] The preferred embodiments of formula 11-C:

[0371] 246. Z₁, Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ are independently CR₂; Y₁ isN; Y₂ is C; Any one of Z₁, Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉ must be a carbonatom to which the remainder of the molecule is attached.

[0372] 247. Z₁, Z₂, Z₃, Z₄, Z₇, Z₈, Z₉ are independently CR₂; Z₆ is O,S, N—R₁; Y₁ is C; Y₂ is N; Any one of Z₁, Z₂, Z₃, Z₄, Z₆, Z₇, Z₈, Z₉must be a carbon atom to which the remainder of the molecule isattached.

[0373] The preferred embodiments of formula 12-A:

[0374] 248. Z₁, Z₂, Z₃, Z₄ are independently CR₂; Z₅ is O, S, N—R₁; W₁,W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring. In the ring formed by W₁, W₂, W₃ one double bond might be present;t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁, Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0375] 249. Z₁, Z₂, Z₃, Z₄ are independently CR₂; Z₅ is N, CR₂; W₁, W₂,W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring; Inthe ring formed by W₁, W₂, W₃ one double bond might be present; t=1-4;Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0376] 250. Z₁, Z₂, Z₃, Z₄ are independently CR₂; Z₅ is O, S, N; W₁, W₂,W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring; Inthe ring formed by W₁, W₂, W₃ one double bond might be present; t=1-3;Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0377] 251. Z₁ is N; Z₂, Z₃, Z₄ are independently CR₂; Z₅ is O, S, N—R₁;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₂, Z₃, Z₄ must be acarbon atom to which the remainder of the molecule is attached.

[0378] 252. Z₁, Z₂ are N; Z₃, Z₄ are independently CR₂; Z₅ is O, S,N—R₁; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₃, Z₄ must be acarbon atom to which the remainder of the molecule is attached.

[0379] 253. Z₁, Z₃ are N; Z₂, Z₄ are independently CR₂; Z₅ is O, S,N—R₁; Z₁, Z₂ are N; Z₃, Z₄ are independently CR₂; Z₅ is N, CR₂; W₁, W₂,W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring; Inthe ring formed by W₁, W₂, W₃ one double bond might be present; t=1-4;Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₂, Z₄ must be a carbon atom towhich the remainder of the molecule is attached.

[0380] 254. Z₁, Z₄ are N; Z₂, Z₃ are independently CR₂; Z₅ is O, S,N—R₁; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₂, Z₃ must be acarbon atom to which the remainder of the molecule is attached.

[0381] 255. Z₁ is N; Z₂, Z₃, Z₄ are independently CR₂; Z₅ is N, CR₂; W₁,W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; In the ring formed by W₁, W₂, W₃ one double bond might be present;t=1-4; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0382] 256. Z₁, Z₃ are N; Z₂, Z₄ are independently CR₂; Z₅ is N, CR₂;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₂, Z₄ must bea carbon atom to which the remainder of the molecule is attached.

[0383] 257. Z₁, Z₄ are N; Z₂, Z₃ are independently CR₂; Z₅ is N, CR₂;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₂, Z₃ must bea carbon atom to which the remainder of the molecule is attached.

[0384] 258. Z₁, Z₂ are N; Z₃, 14 are independently CR₂; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₃, Z₄ must bea carbon atom to which the remainder of the molecule is attached.

[0385] 259. Z₁, Z₃ are N; Z₂, Z₄ are independently CR₂; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₂, Z₄ must bea carbon atom to which the remainder of the molecule is attached.

[0386] 260. Z₁, Z₄ are N; Z₂, Z₃ are independently CR₂; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₂ Z₃ must be acarbon atom to which the remainder of the molecule is attached.

[0387] 261. Z₂ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₅ is O, S, N—R₁;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁, Z₃, Z₄ must be acarbon atom to which the remainder of the molecule is attached.

[0388] 262. Z₂, Z₃ are N; Z₁, Z are independently CR₂; Z₅ is O, S, N—R₁;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁, Z₄ must be acarbon atom to which the remainder of the molecule is attached.

[0389] 263. Z₂, Z₄ are N; Z₁, Z₃ are independently CR₂; Z₅ is O, S,N—R₁; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁, Z₃ must be acarbon atom to which the remainder of the molecule is attached.

[0390] 264. Z₂ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₅ is N, CR₂; W₁,W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; In the ring formed by W₁, W₂, W₃ one double bond might be present;t=1-; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₃, Z must be a carbonatom to which the remainder of the molecule is attached.

[0391] 265. Z₂, Z₃ are N; Z₁, Z₄ are independently CR₂; Z₅ is N, CR₂;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₄ must bea carbon atom to which the remainder of the molecule is attached.

[0392] 266. Z₂, Z₄ are N; Z₁, Z₃ are independently CR₂; Z₅ is N, CR₂;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₃ must bea carbon atom to which the remainder of the molecule is attached.

[0393] 267. Z₂ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₃, Z₄ mustbe a carbon atom to which the remainder of the molecule is attached.

[0394] 268. Z₂, Z₃ are N; Z₁, Z₄ are independently CR₂; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₄ must bea carbon atom to which the remainder of the molecule is attached.

[0395] 269. Z₂, Z₄ are N; Z₁, Z₃ are independently CR₂; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₃ must bea carbon atom to which the remainder of the molecule is attached.

[0396] 270. Z₃ is N; Z₁, Z₂, Z are independently CR₂; Z₅ is O, S, N—R₁;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁, Z₂, Z must be acarbon atom to which the remainder of the molecule is attached.

[0397] 271. Z₃, Z₄ are N; Z₁, Z₄ are independently CR₂; Z₅ is O, S,N—R₁; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁, Z₂ must be acarbon atom to which the remainder of the molecule is attached.

[0398] 272. Z₃ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₅ is N, CR₂; W₁,W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; In the ring formed by W₁, W₂, W₃ one double bond might be present;t=1-4; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₂, Z must be a carbonatom to which the remainder of the molecule is attached.

[0399] 273. Z₃, Z₄ are N; Z₁, Z₂ are independently CR₂; Z₅ is N, CR₂;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₂ must bea carbon atom to which the remainder of the molecule is attached.

[0400] 274. Z₃ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₂, Z₄ mustbe a carbon atom to which the remainder of the molecule is attached.

[0401] 275. Z₃, Z₄ are N; Z₁, Z are independently CR₂; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₂ must bea carbon atom to which the remainder of the molecule is attached.

[0402] 276. Z₁, Z₂, Z₃ are independently CR₂; Z₄ is N; Z₅ is O, S, N—R₁;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring. In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-4; Y₁, Y₂, Y₃, Y₄ are C; Any one of Z₁, Z₂, Z₃, must bea carbon atom to which the remainder of the molecule is attached.

[0403] 277. Z₁, Z₂, Z₃ are independently CR₂; Z₄ is N; Z₅ is N, CR₂; W₁,W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; In the ring formed by W₁, W₂, W₃ one double bond might be present;t=1-4; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₂, Z₃ must be a carbonatom to which the remainder of the molecule is attached.

[0404] 278. Z₁, Z₂, Z₃ are independently CR₂; Z₄ is N; Z₅ is O, S. N;W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; In the ring formed by W₁, W₂, W₃ one double bond mightbe present; t=1-3; Y₁, Y₂, Y₃ are C; Y₄ is N; Any one of Z₁, Z₂. Z₃, Z₄must be a carbon atom to which the remainder of the molecule isattached.

[0405] The preferred embodiments of formula 12-B:

[0406] 279. Z₁, Z₂, Z₃. Z₄ are independently CR₂; Z₅ is O, S, N—R₁; Y₁,Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0407] 280. Z₁ is N; Z₂, Z₃, Z₄ are independently CR₂; Z₅ is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0408] 281. Z₁, Z₂ are N; Z₃, Z₄ are independently CR₂; Z₅ is O, S,N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r(r=0-2), O, N—R₁ with the proviso that no S—S, S—O or O—O bond formationcan occur to form a saturated ring; t=1-3. Any one of Z₃, Z₄ must be acarbon atom to which the remainder of the molecule is attached.

[0409] 282. Z₁, Z₃ are N; Z₂, 14 are independently CR₂; Z₅ is O, S,N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r(r=0-2), O, N—R₁ with the proviso that no S—S, S—O or O—O bond formationcan occur to form a saturated ring; t=1-3. Any one of Z₂, Z₄ must be acarbon atom to which the remainder of the molecule is attached.

[0410] 283. Z₂ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₅ is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0411] 284. Z₂, Z₃ are N; Z₁, Z₄ are independently CR₂; Z₅ is O, S,N—R₁; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r(r=0-2), O, N—R₁ with the proviso that no S—S, S—O or O—O bond formationcan occur to form a saturated ring; t=1-3. Any one of Z₁, Z₄ must be acarbon atom to which the remainder of the molecule is attached.

[0412] 285. Z₃ is N; Z₁, Z₂, Z are independently CR₂; Z₅ is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₁, Z₂. Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0413] 286. Z₁, Z₂, Z₃, Z₅ are independently CR₂; Z₄ is O, S, N—R₁; Y₁,Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0414] 287. Z₁ is N; Z₂, Z₃, Z₅ are independently CR₂; Z is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0415] 288. Z₁, Z₂ are N; Z₃, Z₅ are independently CR₂; 4 is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₃, Z₅ must be a carbon atomto which the remainder of the molecule is attached.

[0416] 289. Z₁, Z₃ are N; Z₂, Z₅ are independently CR₂; Z is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₂, Z₅ must be a carbon atomto which the remainder of the molecule is attached.

[0417] 290. Z₂ is N; Z₁, Z₃, Z₅ are independently CR₂; Z₄ is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0418] 291. Z₂, Z₃ are N; Z₁, Z₅ are independently CR₂; Z is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₁, Z₅ must be a carbon atomto which the remainder of the molecule is attached.

[0419] 292. Z₃ is N; Z₁, Z₂, Z₅ are independently CR₂; Z₄ is O, S, N—R₁;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0420] 293. Z₁, Z₂, Z₃, Z. Z₅ are independently CR₂; Y₁, Y₂, Y₃ are C;Y₄ is N; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; t=1-3. Any one of Z₁, Z₂, Z₃ Z must be a carbon atom towhich the remainder of the molecule is attached.

[0421] 294. Z₁ is N; Z₂, Z₃, Z₄, Z₅ are independently CR₂; Y₁, Y₂, Y₃are C; Y₄ is N; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0422] 295. Z₁, Z₂ are N; Z₃, Z₄, Z₅ are independently CR₂; Y₁, Y₂, Y₃are C; Y₄ is N; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₃, Z₄ must be a carbon atom towhich the remainder of the molecule is attached.

[0423] 296. Z₁, Z₃ are N; Z₂, 4, Z₅ are independently CR₂; Y₁, Y₂, Y₃are C; Y₄ is N; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0424] 297. Z₂ is N; Z₁, Z₃, Z, Z₅ are independently CR₂; Y₁, Y₂, Y₃ areC; Y₄ is N; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; t=1-3. Any one of Z₁, Z₃, Z₄ must be a carbon atom towhich the remainder of the molecule is attached.

[0425] 298. Z₂, Z₃ are N; Z₁, Z, Z₅ are independently CR₂; Y₁, Y₂, Y₃are C; Y₄ is N; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0426] 299. Z₃ is N; Z₁, Z₂, Z, Z₅ are independently CR₂; Y₁, Y₂, Y₃ areC; Y₄ is N; W₁, W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; t=1-3. Any one of Z₁, Z₂, Z₄, Z₅ must be a carbon atomto which the remainder of the molecule is attached.

[0427] The preferred embodiments of formula 13-A:

[0428] 300. Z₁, Z₂, Z₃, Z, Z₅, Z₆ are independently N, CR₂; Y₁, Y₂, Y₃,Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂ Z₃, Z₄, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0429] 301. Z₁ is N; Z₂, Z₃, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0430] 302. Z₁, Z₂ are N; Z₃, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₃, Z₄ Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0431] 303. Z₁, Z₃ are N; Z₂, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₁. Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0432] 304. Z₁, Z₄ are N; Z₂, Z₃, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0433] 305. Z₁, Z₅ are N; Z₂, Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0434] 306. Z₁, Z₆ are N; Z₂, Z₃, Z₄, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0435] 307. Z₂ is N; Z₁, Z₃, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, 14, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0436] 308. Z₂, Z₃ are N; Z₁, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₄, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0437] 309. Z₂, Z₄ are N; Z₁, Z₃, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0438] 310. Z₂, Z₅ are N; Z₁, Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0439] 311. Z₂, Z₅ are N; Z₁, Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0440] 312. Z₂, Z₆ are N; Z₁, Z₃, Z₄, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0441] 313. Z₃ is N; Z₁, Z₂ 14, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₄. Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0442] 314. Z₃, Z₄ are N; Z₁. Z₂, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0443] 315. Z₃, Z₅ are N; Z₁, Z₂, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0444] 316. Z₃, Z₆ are N; Z. Z₂, Z, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂ Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0445] 317. L is N; Z₁, Z₂ Z₃, Z₅, Z₆ are independently CR₂; Y₁, Y₂, Y₃,Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0446] 318. Z₄, Z₅ are N; Z₁, Z₂, Z₃, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0447] 319. Z₅ is N; Z₁, Z₂, Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃ Z₄, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0448] 320. Z₅, Z₆ are N; Z₁, Z₂, Z₃, Z₄ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0449] 321. Z₆ is N; Z₁, Z₂, Z₃, Z, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄, Z₅ must be acarbon atom to which the remainder of the molecule is attached.

[0450] The preferred embodiments of formula 13-B:

[0451] 322. Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ are independently N, CR₂; Y₁, Y₂, Y₃,Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ must bea carbon atom to which the remainder of the molecule is attached.

[0452] 323. Z₁ is N; Z₂, Z₃, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0453] 324. Z₁, Z₂ are N; Z₃, Z₄, Z_(5, 14) are independently CR₂; Y₁,Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O,N—R₁ with the proviso that no S—S, S—O or O—O bond formation can occurto form a saturated ring; t=1-3. Any one of Z₃, Z₄. Z₅, Z₁ must be acarbon atom to which the remainder of the molecule is attached.

[0454] 325. Z₁, Z₃ are N; Z₂, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₄, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0455] 326. Z₁, Z₄ are N; Z₂, Z₃, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₅, Z₁ must be a carbonatom to which the remainder of the molecule is attached.

[0456] 327. Z₁, Z₅ are N; Z₂, Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₁ must be a carbonatom to which the remainder of the molecule is attached.

[0457] 328. Z₁, Z₆ are N; Z₂, Z₃, Z₄, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0458] 329. Z₂ is N; Z₁, Z₃. Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0459] 330. Z₂, Z₃ are N; Z₁, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₄, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0460] 331. Z₂, Z₄ are N; Z₁, Z₃, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0461] 332. Z₂, Z₅ are N; Z₁, Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0462] 333. Z₂, Z₅ are N; Z₁, Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0463] 334. Z₂, Z₆ are N; Z₁, Z₃, Z₄, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0464] 335. Z₃ is N; Z₁, Z₂, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₄, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0465] 336. Z₃, Z₄ are N; Z₁, Z₂, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0466] 337. Z₃, Z₅ are N; Z₁, Z₂, Z, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂. Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0467] 338. Z₃, Z₆ are N; Z₁, Z₂, Z, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0468] 339. Z₄ is N; Z₁, Z₂, Z₃, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0469] 340. Z₄, Z₅ are N; Z₁, Z₂, Z₃, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0470] 341. Z₅ is N; Z₁, Z₂. Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0471] 342. Z₅, Z₆ are N; Z₁, Z₂, Z₃, Z₄ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄ must be a carbonatom to which the remainder of the molecule is attached.

[0472] 343. Z₆ is N; Z₁, Z₂, Z₃, Z, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄, Z₅ must be acarbon atom to which the remainder of the molecule is attached.

[0473] The preferred embodiments of formula 13-C:

[0474] 344. Z₁, Z₂, Z₃, Z, Z₅, Z₆ are independently N, CR₂; Y₁, Y₂, Y₃,Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ must bea carbon atom to which the remainder of the molecule is attached.

[0475] 345. Z₁ is N; Z₂, Z₃, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0476] 346. Z₁, Z₂ are N; Z₃, Z, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₃, Z₄, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0477] 347. Z₁, Z₃ are N; Z₂, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₄. Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0478] 348. Z₁, Z₄ are N; Z₂, Z₃, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0479] 349. Z₁, Z₅ are N; Z₂, Z₃, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0480] 350. Z₁, Z₆ are N; Z₂ Z₃, Z₄, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0481] 351. Z₂ is N; Z₁, Z₃, Z₄, Z₅, Z₆ are independently CR₂; Y., Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄ Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0482] 352. Z₂, Z₃ are N; Z₁, Z₄, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₄, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0483] 353. Z₂, Z₄ are N; Z₁, Z₃, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0484] 354. Z₂, Z₅ are N; Z₁, Z₃, Z, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃. Z, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0485] 355. Z₂, Z₅ are N; Z₁, Z₃, 74, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃ Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0486] 356. Z₂, Z₆ are N; Z₁, Z₃, Z₄, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0487] 357. Z₃ is N; Z₁, Z₂, Z, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₄, Z₅, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0488] 358. Z₃, Z₄ are N; Z₁, Z₂, Z₅, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₅, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0489] 359. Z₃, Z₅ are N; Z₁, Z₂, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₄, Z₆ must be a carbonatom to which the remainder of the molecule is attached.

[0490] 360. Z₃, Z₆ are N; Z. Z₂, Z₄, Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₄, Z₅ must be a carbonatom to which the remainder of the molecule is attached.

[0491] 361. Z₄ is N; Z₁, Z₂, Z₃, Z₅ , Z ₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₁, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0492] 362. Z₄, Z₅ are N; Z₁, Z₂, Z₃, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂. Z_(3, 1)Z₅ Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0493] 363. Z₅ is N; Z₁, Z₂. 14, Z₄, Z₆ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z. Z₄, Z₆ must be acarbon atom to which the remainder of the molecule is attached.

[0494] 364. Z₅, Z₆ are N; Z₁, Z₂, Z₃, Z₄ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z_(3, 14) must be acarbon atom to which the remainder of the molecule is attached.

[0495] 365. Z₆ is N; Z₁, Z₂, Z_(3, 4), Z₅ are independently CR₂; Y₁, Y₂,Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₃, Z₄, Z₅ must be acarbon atom to which the remainder of the molecule is attached.

[0496] The preferred embodiments of formula 14-A and 14-B:

[0497] 366. Z₁ is N; Z₂, Z, 14, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₄, Z₅, Z₆,Z₇, Z₈ must be a carbon atom to which the remainder of the molecule isattached.

[0498] 367. Z₁, Z₂ are N; Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₃, Z, Z₅, Z₆, Z₇, Z₈must be a carbon atom to which the remainder of the molecule isattached.

[0499] 368. Z₁, Z₃ are N; Z₂, Z₄, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₂, Z₄, Z₅, Z₆, Z₇, Z₈must be a carbon atom to which the remainder of the molecule isattached.

[0500] 369. Z₁, Z₄ are N; Z₂, Z₃, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₂, Z₃, Z₅, Z₆, Z₇, Z₈must be a carbon atom to which the remainder of the molecule isattached.

[0501] 370. Z₁, Z₂ are N; Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₃, Z₄, Z₅, Z₆, Z₇, Z₈must be a carbon atom to which the remainder of the molecule isattached.

[0502] 371. Z₁ is N; Z₂, Z₃, Z₄ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-3. Any one of Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ must be a carbon atom towhich the remainder of the molecule is attached.

[0503] 372. Z₁, Z₂ are N; Z, Z₄ are independently CR₂; Z, Z₆, Z₇, Z₈ areindependently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independentlyCR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that no S—S, S—O or O—Obond formation can occur to form a saturated ring; t=1-3. Any one ofZ_(3, 4), Z₅, Z₆, Z₇, Z₈ must be a carbon atom to which the remainder ofthe molecule is attached.

[0504] 373. Z₁, Z₃ are N; Z₂, Z₄ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-3. Any one of Z₂, Z, Z₅, Z₆, Z₇, Z₈ must be a carbon atom to whichthe remainder of the molecule is attached.

[0505] 374. Z₁, Z are N; Z₂, Z₃ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-3. Any one of Z₂, Z₃, Z₅, Z₆, Z₇, Z₈ must be a carbon atom to whichthe remainder of the molecule is attached.

[0506] 375. Z₁, Z₂ are N; Z₃, Z₄ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-3. Any one of Z₃, Z, Z₅, Z₆, Z₇, Z₈ must be a carbon atom to whichthe remainder of the molecule is attached.

[0507] 376. Z₂ is N; Z₁, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₄, Z₅, Z₆,Z₇, Z₈ must be a carbon atom to which the remainder of the molecule isattached.

[0508] 377. Z₂, Z are N; Z₁, Z, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₅, Z₆, Z₇, Z₈must be a carbon atom to which the remainder of the molecule isattached.

[0509] 378. Z₂, A are N; Z₁, Z₃, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₁, Z₃, Z₅, Z₆, Z₇, Z₈must be a carbon atom to which the remainder of the molecule isattached.

[0510] 379. Z₂ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-3. Any one of Z₁, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ must be a carbon atom towhich the remainder of the molecule is attached.

[0511] 380. Z₂, Z₃ are N; Z₁, Z₄ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-3. Any one of Z₁, Z₄, Z₅, Z₆, Z₇, Z₈ must be a carbon atom to whichthe remainder of the molecule is attached.

[0512] 381. Z₂, Z₄ are N; Z₁, Z₃ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-3. Any one of Z₁, Z, Z₅, Z₆, Z₇, Z₈ must be a carbon atom to whichthe remainder of the molecule is attached.

[0513] 382. Z₃ is N; Z₁, Z₂, Z₄, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₄, Z₅, Z₆,Z₇, Z₈ must be a carbon atom to which the remainder of the molecule isattached.

[0514] 383. Z₃, Z₄ are N; Z₁, Z₂, Z₅, Z₆, Z₇, Z₈ are independently CR₂;Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ are independently CR₄R₄, S(O)r (r=0-2),O, N—R₁ with the proviso that no S—S, S—O or O—O bond formation canoccur to form a saturated ring; t=1-3. Any one of Z₁, Z₂, Z₅, Z₆, Z₇, Z₈must be a carbon atom to which the remainder of the molecule isattached.

[0515] 384. Z₄ is N; Z₁, Z₃, Z₄ are independently CR₂; Z₅, Z₆, Z₇, Z₈are independently N, CR₂; Y₁, Y₂, Y₃, Y₄ are C; W₁, W₂, W₃ areindependently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-3. Any one of Z₁, Z₃, Z₄, Zs, Z₆, Z₇, Z₈ must be a carbon atom towhich the remainder of the molecule is attached.

[0516] The preferred embodiments of formula 15-A:

[0517] 385. Z₁ is N; Z₂, Z₃, Z₄ are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, a bond;W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁,; t=0-2; W₃, W₄, W₅ areindependently O, S (O)r (r=0-2), CR₄R₄, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;u=1-3; Any one of Z₂, Z₃, Z₄ must be a carbon atom to which theremainder of the molecule is attached.

[0518] 386. Z₁, Z₂ are N; Z₃, Z₄ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, abond; W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; t=0-2; W₃, W₄, W₅ areindependently O, S (O)r (r=0-2), CR₄R₄, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;u=1-3; Any one of Z₃, Z₄ must be a carbon atom to which the remainder ofthe molecule is attached.

[0519] 387. Z₁, Z₃ are N; Z₂, A are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, a bond;W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; t=0-2; W₃, W₄, W₅ are independentlyO, S (O)r (r=0-2), CR₄R₄, N—R₁ with the proviso that no S—S, S—O or O—Obond formation can occur to form a saturated ring; u=1-3; Any one of Z₂,Z₄ must be a carbon atom to which the remainder of the molecule isattached.

[0520] 388. Z₁, Z₄ are N; Z₂, Z₃ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, abond; W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; t=0-2; W₃, W₄, W₅ areindependently O, S (O)r (r=0-2), CR₄R₄, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;u=1-3; Any one of Z₂, Z₃ must be a carbon atom to which the remainder ofthe molecule is attached.

[0521] 389. Z₂ is N; Z₁, Z₃, Z are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, a bond;W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁,; t=0-2; W₃, W₄, W₅ areindependently O, S (O)_(r) (r=0-2), CR₄R₄, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;u=1-3; Any one of Z₁, Z₃, Z₄ must be a carbon atom to which theremainder of the molecule is attached.

[0522] 390. Z₂, Z₃ are N; Z₁, Z₄ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, abond; W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; t=0-2; W₃, W₄, W₅ areindependently O, S (O)_(r) (r=0-2), CR₄R₄, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;u=1-3; Any one of Z₁, Z₄ must be a carbon atom to which the remainder ofthe molecule is attached.

[0523] 391. Z₂, Z₄ are N; Z₁, Z₃ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, abond; W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; t=0-2; W₃, W₄, W₅ areindependently O, S (O)r (r=0-2), CR₄R₄, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;u=1-3; Any one of Z₁, Z₃ must be a carbon atom to which the remainder ofthe molecule is attached.

[0524] 392. Z₃ is N; Z₁, Z₂, Z are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, a bond;W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; t=0-2; W₃, W₄, W₅ are independentlyO, S (O)r (r=0-2), CR₄R₄, N—R₁ with the proviso that no S—S, S—O or O—Obond formation can occur to form a saturated ring; u=1-3; Any one of Z₁,Z₂, Z₄ must be a carbon atom to which the remainder of the molecule isattached.

[0525] 393. Z₃, Z₄ are N; Z₁, Z₂ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, abond; W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; t=0-2; W₃, W₄, W₅ areindependently O, S (O)r (r=0-2), CR₄R₄, N—R₁ with the proviso that noS—S, S—O or O—O bond formation can occur to form a saturated ring;u=1-3; Any one of Z₁, Z₂ must be a carbon atom to which the remainder ofthe molecule is attached.

[0526] 394. Z₄ is N; Z₁, Z₂ Z₃ are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁, a bond;W₂ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; t=0-2; W₃, W₄, W₅ are independentlyO, S (O)r (r=0-2), CR₄R₄, N—R₁ with the proviso that no S—S, S—O or O—Obond formation can occur to form a saturated ring; u=1-3; Any one of Z₁,Z₂, Z₃ must be a carbon atom to which the remainder of the molecule isattached.

[0527] The preferred embodiments of formula 15-B

[0528] 395. Z₁ is N; Z₂, Z₃ Z₄ are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂, W₃,W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-2; u=1-3; Any one of Z₂, Z₃, Z₄ must be a carbon atom to which theremainder of the molecule is attached.

[0529] 396. Z₁, Z₂ are N; Z₃, Z₄ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂,W₃, W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; t=1-2; u=1-3; Any one of Z₃, Z₄ must be a carbon atom to which theremainder of the molecule is attached.

[0530] 397. Z₁, Z₃ are N; Z₂, 4 are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂, W₃,W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-2; u=1-3; Any one of Z₂, Z₄ must be a carbon atom to which theremainder of the molecule is attached.

[0531] 398. Z₁, Z₄ are N; Z₂, Z₃ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂,W₃, W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; t=1-2; u=1-3; Any one of Z₂, Z₃ must be a carbon atom to which theremainder of the molecule is attached.

[0532] 399. Z₂ is N; Z₁, Z₃ Z are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂, W₃,W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-2; u=1-3; Any one of Z₁, Z₃, Z₄ must be a carbon atom to which theremainder of the molecule is attached.

[0533] 400. Z₂, Z₃ are N; Z₁, Z₄ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂,W₃, W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; t=1-2; u=1-3; Any one of Z₁, Z₄ must be a carbon atom to which theremainder of the molecule is attached.

[0534] 401. Z₂, Z₄ are N; Z₁ Z₃ are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂, W₃,W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-2; u=1-3; Any one of Z₁, Z₃ must be a carbon atom to which theremainder of the molecule is attached.

[0535] 402. Z₃ is N; Z₁, Z₂, 4 are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂, W₃,W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-2; u=1-3; Any one Z₁, Z₂, Z₄ of must be a carbon atom to which theremainder of the molecule is attached.

[0536] 403. Z₃, Z₄ are N; Z₁, Z₂ are independently CR₂; Y₁, Y₂ are C;Y₃, Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂,W₃, W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; t=1-2; u=1-3; Any one of Z₁, Z₂ must be a carbon atom to which theremainder of the molecule is attached.

[0537] 404. Z₄ is N; Z₁, Z₂, Z₃ are independently CR₂; Y₁, Y₂ are C; Y₃,Y₄ are independently CH, N; W₁ is O, S(O)r (r=0-2), CR₄R₄, N—R₁; W₂, W₃,W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-2; u=1-3; Any one Z₁, Z₂, Z₃ of must be a carbon atom to which theremainder of the molecule is attached.

[0538] The preferred embodiments of formula 15-C:

[0539] 405. Z₁, Z₂, Z₃ are independently CR₂; Y₁, Y₂, Y₄ are C; Y₂ is N;W₁, W₂, W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; t=1-2; u=1-2; Any one Z₁, Z₂, Z₃ of must be a carbonatom to which the remainder of the molecule is attached.

[0540] 406. Z₁ is N; Z₂, Z₃ are independently CR₂; Y₁, Y₂, Y₄ are C; Y₂is N; W₁, W₂, W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; t=1-2; u=1-2; Any one Z₂, Z₃ of must be a carbon atom towhich the remainder of the molecule is attached.

[0541] 407. Z₁, Z₃ are N; Z₃ is CR₂; Y₁, Y₂, Y₄ are C; Y₂ is N; W₁, W₂,,W₄ are independently O, S(O)r (r=0-2), CR₄R₄, N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring;t=1-2; u=1-2; Z₃ is the carbon atom to which the remainder of themolecule is attached.

[0542] The preferred tricyclic heteroarylgroup A and B are one of thefollowing formulae: 1-A, 1-B, 2-A, 3-B, 4-B, 5-A, 5-B, 6-B, 6-C, 7-B,8-B, 9-A, 10-A, 12-A, 12-B, 13-B, 14-A, 14-B, and 15-B.

[0543] More preferred compounds of the present invention are:

[0544] 1.(5R,6Z)-6-(Imidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0545] 2.(5R,6Z)-6-[(7-methoxyimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0546] 3.(5R,6Z)-6-[(7-chloroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0547] 4. (5R),(6Z)-6-Imidazo[1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0548] 5. (5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0549] 6. (5R),(6Z)-6-(Imidazo[1.2-a]quinoxaline-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hepto-2-ene-2-carboxylicacid, sodium salt;

[0550] 7.(5R,6Z)-6-[(7-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0551] 8. (5R),(6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid sodium salt;

[0552] 9.(5R,6E)-6-[(10-benzyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-8-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0553] 10.6-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0554] 11. (5R,6E&Z)-7-oxo-6-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0555] 12. (5R),(6Z)-6-(5H-Imidazo[2,1-a]isoindol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid sodium salt;

[0556] 13.(5R,6Z)-6-[(5-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0557] 14.(5R,6Z)-6-[(7-fluoroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0558] 15. (5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

[0559] 16. (5R),(6Z)-6-(imidazo[2,1-b]bebzothiazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0560] 17. (5R),(6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0561] 18. (5R),(6Z)-6-(7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-6-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

[0562] 19. (5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0563] 20.(5R),(6Z)-8-[(9-methyl-9H-imidazo[1,2-a]benzimidazol-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid;

[0564] 21.(5R,6Z)-7-oxo-6-(4H-thieno[2′,3′:4,5]thiopyrano[2,3-b]pyridin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid (Sodium salt);

[0565] 22.(5R,6Z)-6-[(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0566] 23.(5R,6Z)-6-{[7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0567] 24.(5R,6Z)-6-(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolo[1,5-a]quinazolin]-2′-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0568] 25.(5R,6Z)-6-[(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0569] 26.(5R,6Z)-6-[(5-methoxy-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0570] 27.(5R,6Z)-6-({5-[2-(benzyloxy)ethoxy]-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl}methylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0571] 28.(5R,6Z)-6-(2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0572] 29.(5R,6Z)-6-(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0573] 30.(5R,6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0574] 31.(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)-4-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt;

[0575] 32.(5R,6Z)-7-oxo-6-(5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; and

[0576] 33. (5R,6Z)-6-{[6-(ethoxycarbonyl)-5,6,7,8-tetrahydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt.

[0577] Especially preferred compounds of the present invention are:

[0578](5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; and

[0579](5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.

[0580] A compound's structural formula includes any tautomers, anystereoisomers (except where stereochemistry is clearly noted) and anycrystalline forms.

[0581] The compounds according to the present invention have β-lactamaseinhibitory and antibacterial properties and are useful for the treatmentof infections in humans and animals. It should be noted that thecompounds of the present invention, when used in combination withβ-lactam antibiotics will result in the increased antibacterial activity(synergistic effect) against class-A and class-C producing organisms.β-Lactam antibiotics include penicillin antibiotics such aspiperacillin, amoxycillin, ticarcillin, benzylpenicillins, ampicillin,sulbenicillin, other known penicillins and cephalosporins such ascefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin,cephradine, other known cephalosporins, aztreonam and latamoxef(Moxalactam). Most preferably compounds of this present invention areused with piperacillin, and Amoxicillin which has a broad spectrum ofactivity against Gram positive and Gram negative pathogens.

[0582] The administration of the compounds of the present invention maybe provided in conjunction with prior, simultaneous or subsequentadministration of a β-lactam antibiotic (“co-administration”). By“provided”, it is intended to include direct administration as well asin vivo, e.g. pro-drugs. When the compounds of the present invention areco-administered with a β-lactam antibiotic, the ratio of the amount ofthe compound to the amount of the β-lactam antibiotic may vary in a widerange. The ratio of β-lactam antibiotic to β-lactamase inhibitor mayvary from 1:1 to 100:1. Preferably the ratio of the β-lactam antibioticto the β-lactamase inhibitor is less than 10:1. The composition of thepresent invention may be in a form suitable for oral (PO), intravenous(IV) or topical administration. The compositions of the invention may bein a form of tablets, capsules, creams, syrups, suspension, sterilesolutions suitable for injection or infusion. Preferably, the compoundsof the present invention are co-administered with piperacillinintravenously or Amoxicillin orally or intravenously.

[0583] IC₅₀ Determination for the Penem Inhibitor

[0584] β-Lactamase inhibitory activity of the penem inhibitors wasdetermined spectrophotometrically as described by Bush et al., [Bush,K., Macalintal, C., Rasmussen, B. A., Lee, V. and Yang, Y. AntimicrobialAgents and Chemotherapy 1993, 37, 851]. Homogeneously purified class Aβ-lactamases TEM-1 from E. coli and 1 ml-1 from Enterobacter cloacae,class B enzyme CcrA from Bacteroides fragilis and class C enzyme AmpCfrom Enterobacter cloaca were employed in the assay. The enzymeconcentrations for TEM-1, 1 ml-1, CcrA and AmpC were 4.3, 7.1, 1.2 and2.1 nM, respectively. A wide range of inhibitor concentrations wereprepared in 50 mM PO₄, pH 7.0 to include the possible IC₅₀ values. Thesubstrate used to initiate the enzyme reaction was nitrocefin at 50μg/ml in the same buffer as the inhibitor. Initially the enzyme andinhibitor (20 μl each) were preincubated for 10 minutes at 25° C. priorto the addition of 160 μl volume of nitrocefin. Initial rates ofhydrolysis were monitored for 5 minutes at 495 nm using a MolecularDevices Spectra Max 250 with kinetic protocol of SoftMax Program.Readings from the Spectra Max 250 were exported and transferred toMicrosoft Excel. The percent of inhibition of each inhibitorconcentration was calculated based on the control enzyme activity. Theinhibitor concentration that caused a 50% reduction in the enzymaticactivity (IC₅₀) was determined graphically. TABLE 1 β-LactamaseInhibition Data IC50 (nM) Class A Class B Class C Compound TEM-1 Imi CcrAmpC Example 1 10 160 350 1.4 Example 2 18 180 250 2.4 Example 3 5.6 22 74 3.2 Example 4 6 90 900 2.1 Example 5 1.4 72 240 2.1 Example 6 2.5210 350 1.2 Example 7 2.6 106 103 1.1 Example 8 2.4 15 450 1.4 Example 93.5 3600 220 4.5 Example 10 48 35 140 5.8 Example 11 1.4 78  62 3.6Example 12 2.6 6.4  42 .28 Example 13 8.7 102 228 1.6 Example 14 8.1 270370 2.4 Example 15 2.8 100 200 1.5 Example 16 4.5 70 130 9.5 Example 17ND ND ND ND Example 18 ND ND ND ND Example 19 1.9 33 215 0.62 Example 20ND ND ND ND Example 21 11 580 210 3.7 Example 22 ND ND ND ND Example 23ND ND ND ND Example 24 ND ND ND ND Example 25 ND ND ND ND Example 26 4863 420 10 Example 27 12 33 180 3 Example 28 3.2 90 110 5.7 Example 29 15300 240 18 Example 30 46 200  97 9.3 Example 31 4.3 140 130 4 Example 322.6 110 180 5.6 Example 33 10 360 160 140

[0585] Antimicrobial susceptibility testing. The in vitro activities ofthe antibiotics were determined by the microbroth dilution method asrecommended by the National Committee for Clinical Laboratory Standards(NCCLS). (NCCLS. 2000. Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria That Grow Aerobically; Approved Standards: M7-A5,vol. 19. National Committe for Clinical Laboratory Standards, Villanova,Pa.). Mueller-Hinton II broth (MHBII)(BBL Cockeysville, Md.), was usedfor the testing procedure. Microtiter plates containing 50 μl per wellof two-fold serial dilutions of piperacillin combined with a constantamount (4 ug/ml) of a B-lactamase inhibitor (final concentration) wereinoculated with 50 μl of inoculum to yield the appropriate density (10⁵CFU/ml) in 100 μl. The plates were incubated for 18-22 hours at 35° C.in ambient air. The minimal inhibitory concentration (MIC) for allisolates was defined as the lowest concentration of antimicrobial agentthat completely inhibits the growth of the organism as detected by theunaided eye. The MIC data obtained by the above said procedure arelisted in Table 2. TABLE 2 Minimal Inhibitory Concentration (μg/ml)Data: Inc: 35° C. for 18 hours E. Coli E. Coli E. Coli E. Cloacae P.aeruginos S. Marcescens E. Coli GC2847 GC2920 GC2894 GC1477 GC1764GC1781 E. Coli S. aureus Example GC2844 (TEM-1) (IRT-2) (Ampc) (Ampc)(Ampc) Sme-1 + Ampc GC2203 GC2216 1 2 2 2 1 4 8 0.5 2 <0.06 2 2 16 2 164 16 2 1 <0.06 3 2 4 1 2 16 8 1 1 <0.06 4 2 4 2 4 32 8 0.5 2 <0.06 5 24 2 2 16 1 0.5 2 <0.06 6 1 2 0.25 16 16 16 1 0.25 <0.06 7 2 4 2 4 32 160.5 1 <0.06 8 2 8 2 2 64 32 0.5 1 <0.06 9 1 64 2 >64 >64 >64 8 1   0.5 10 2 >64 2 32 >64 64 4 1 <0.06 11 1 8 1 4 32 16 1 1 <0.06 12 2 4 4 4 3264 1 2 <0.06 13 2 8 2 8 32 2 4 2 ND 14 2 8 2 8 32 4 2 2 ND 15 2 4 2 2 164 1 2   0.05 16 2 64 2 32 >64 32 1 4   0.05 17 2 64 4 >64 >64 32 8 2 ND18 2 >64 4 >64 >64 64 4 4 ND 19 2 8 2 4 32 1 8 2    .06 20 4 >64 432 >64 32 2 2 ND 21 2 >64 4 32 >64 64 2 2 ND 22 2 16 4 64 >64 64 4 2 ND23 2 64 2 >64 >64 64 4 2 ND 24 2 64 4 >64 >64 64 8 4 ND 25 2 64 4 >64 6464 8 4 ND 26 2 8 2 16 32 8 2 4 ND 27 2 >64 4 64 >64 64 >64 2 ND 28 2 644 32 >64 64 2 2 ND 29 2 64 4 32 >64 64 2 64 ND 30 2 64 8 32 >64 1 32 2ND 31 2 32 2 16 64 32 2 4 ND 32 2 16 4 32 64 64 2 2    .05 33 2 64 464 >64 >64 2 2 ND

In Vivo Antibacterial Protection

[0586] Materials:

[0587] Animals:

[0588] Female mice strain CD-1, approximately 18-22 grams, were receivedfrom Charles River Laboratories and quarantined 7 days prior to use. Inaddition, mice may be rendered neutropenic using cytoxan for particularstudies.

[0589] Infections:

[0590] Clinical isolates that have been adapted to cause infection inmice, are used in the experiment, including infections with strains ofE. coli, K. pneumoniae, M. morganii, E. cloacae, S. marcescens, C.freundii, staphylococci, streptococci, P. aeruginosa and N. gonorrhoeae.

[0591] PREPARATION: Animals are housed five to a cage with free accessto food and water, in accordance with NIH guidelines.

[0592] Experimental Protocol:

[0593] Mice are challenged by injecting 0.5 ml intraperitoneally or 0.05ml intranasally of a predetermined bacterial inoculum suspended inbroth, saline or hog gastric mucin (supplemented with dried bovinehemoglobin for N. gonorrhoeae). The bacterial inoculum is equivalent to10-100 LD₅₀s of the specific infecting strain and will result in deathof the non-treated control animals within 7 days: “Bacterial Virulencein Mice”. Antibacterial doses (dose concentration prepared by two foldserial dilutions of the antibiotic) are dissolved or suspended in 0.2%aqueous agar or methocel, phosphate buffered saline or an adjuvant areadministered orally, subcutaneously or intravenously in the followingmanner:

[0594] a) Orally or subcutaneously: Dose volume of 0.5 ml administered1/2 hr after infection. A second dose may be administered 3 hr. afterinfection for treatment of infections with more virulent organisms.

[0595] b) Intravenously: Dose volume of 0.2 ml, administered ½ hr. afterinfection. For the treatment of infections with more virulent organisms,more doses, up to 48 hr may be administered. (Intravenous dosing willnot exceed 3 doses/24 hr period.)

[0596] c) Oral pretreatment: Under special circumstances, the pH of thestomach needs to be adjusted in order to increase the gastric stabilityof the antibiotic. For this purpose, 0.5 ml of phosphate buffered saline(pH 7.8, 0.06M) (or specific approved adjuvant) is administered orally ½hr after infection, followed 5 minutes later by 0.5 ml of antibiotic(also orally) contained in phosphate buffered saline (pH 7.8, 0.06M).

[0597] Animal Species

[0598] A detailed explanation as to the number of animals needed for thedetermination of in vivo efficacy follows:

[0599] A) Novel antibiotics are tested at 5 different dose levels with 5mice per dose level at each of three routes of administration (oral,subcutaneous and intravenous). Initially the three routes ofadministration should be investigated so as to determine if the drug isorally absorbed and/or which is the most effective route. This wouldrequire 25 mice/route with 3 routes/antibiotic or 75 mice per novelcompound tested. One to two novel antibiotics will be tested perexperiment (75-150 mice)

[0600] B) The effectiveness of the new compound must be compared to thatof a standard, or antibiotic of known effectiveness. Known or previouslytested antibiotics are tested at 5 dose levels with 5 mice per doselevel by a single route of administration, for a total of 25mice/antibiotic. Usually 3-6 antibiotics will be tested per experiment.(75-150 mice).

[0601] C) Untreated controls—In each of the above tests, untreatedanimals are infected with 3 different concentrations of bacterialinoculum with 10 mice per concentration (30 mice total in each and everytest). These untreated controls are used to determine and maintain theinfection level between 10-100 LD50s as required for test to testcomparison and validity.

[0602] Determination of Protective Effects of Antibacterial Agents:

[0603] The protective effects of the antibacterial agent(s) are measuredby the survival of the infected untreated as compared to the treatedanimals. For this determination, animals are observed for 7 days aftertreatment. A census of survivors is taken twice daily and at that timedead as well as moribund animals are removed. The 7 day survival ratiofrom three separate tests are pooled for estimation of median effectivedose (ED50) by computerized program for probit analysis (Cleeland, R.and E. Squires. 91. Evaluation of New Antimicrobials in Vitro and inExperimental Animal Infections. In Antibiotics in Laboratory Medicine”,3rd. ed., edited by Victor Lorian. Williams and Wilkins Baltimore, Md.pp. 752-783). The test is performed three times on separate days toprovide a statistically valid number of animals and to minimizevariation in test results on a day to day and test to test basis. TABLE3 Example ED₅₀ mg/kg Ratio of Piperacillin Inhibitor 1 32-64 2:1 2 >64 2:1 3 32-64 4:1 4 32-64 2:1 5   19.5 4:1 6 NT 7 137  4:1 8 16-64 4:1 9NT 10   55.6 4:1 11 NT 12 50 4:1 13 ND 14 >64  15 25 16 ND 17 ND 18 ND19 63 20 ND 21 ND 22 ND 23 ND 24 ND 25 ND 26 ND 27 ND 28 ND 29 ND 30 ND31 ND 32 ND 33 ND

[0604] Compounds of the general formula I can be prepared by a novel,mild and a facile way, by condensing an appropriately substitutedaldehyde 4 with a 6-bromo-penem derivative of structure I (Scheme 1) inthe presence of anhydrous MgBr₂ or MgBr₂: etherate and base such astriethylamine, DMAP or DBU, preferably at −20° C. to −40° C. Theintermediate aldol product 5 can be functionalized with acid chloridesor anhydrides to an acetate, triflate or a tosylate 6. Compound 6 can besmoothly converted to the desired product by a reductive eliminationprocess using a metal such as activated zinc and phosphate buffer at 20°C. to 35° C. at a pH of 6.5 to 8.0. If the protecting group on thecarboxylate oxygen is a para-nitrobenzyl substitiuent then the reductiveelimination and deprotection can be achieved by a single step. However,if the protecting group is other than a para-nitrobenzyl substituent, atwo step

[0605] procedure can be followed depending up on the nature of theprotecting group. In an alternate procedure, the intermediate 6 can behydrogenated at 40 Psi pressure in the presence of 10% Pd/C. The productcan be isolated as a free acid or as an alkali metal salt. The abovementioned two step procedure can be carried out in one step by carryingout the entire process without isolating the intermediate 6. This is avery general, relatively simple and efficient procedure in terms ofyield and economic feasibility. This procedure can be adopted to largescale synthesis and is amenable to a variety of aldehydes. The abovementioned aldol condensation reaction is very versatile and it can beapplied to any bromopenem derivative, where the carboxy group isprotected other than 4-nitrobenzyl moiety. Example of other protectinggroup include benzyl, para-methoxy benzyl derivative, benzyhydrol,trityl, alkyl and allyl derivatives. However, when the protecting groupis other than 4-nitrobenzyl group, a separate deprotection step need tobe carried out after the reductive elimination procerdure. The chemistryinvolved in the deprotection step is well known to people who areskilled in that art.

[0606] The required aldehydes 4 for the above mentioned transformationscan be prepared from their respective alcohol derivatives by MnO₂oxidation or by Swern oxidation. In some cases the required aldehydefunctionality can be introduced directly in the heterocyclic moiety by aVilsmier Haack reaction using DMF/POCl₃. The aldehydes required for thepresent investigation may be prepared as depicted in Schemes 2 to 8.This procedure can be adopted to any system where there is an aminofunctionality adjacent to the —N═ system. For example, the aldehyderequired to synthesize compound in Example 12, was prepared startingfrom 2-aminophenyl acetonitrile (Scheme 6).

[0607] 2-Amino- condensed thiazole ring systems (Exemplified with thepreparation ofethyl-6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b]thiazole-2-carboxylate,Example 5) can be prepared by reacting cyclic α-halo ketones withthiourea. Scheme 7)

[0608] The aldehyde required to prepare example 10, can be synthesizedby following the procedure outlined in Scheme 8. This procedure can beadopted to prepare a variety of condensed tricyclic imidazolo pyrimidinering systems. The other examples that are enlisted here Examples 13 to33 were prepared by the route enlisted in Schemes 9 to 16.

Experimentals Example 1 Preparation of(5R,6Z)-6-(Imidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid.

[0609] Step 1: Ethyl imidazo[2,1-b]-benzthiazole-2-carboxylate:

[0610] Ethyl bromopyruvate (9.8 g, 50 mmol) was added dropwise to astirred solution of 2-aminobenzothiazole (7.5 g, 50 mmol) in DMF (100ml) at room temperature. After the addition, the reaction mixture washeated to reflux for 6 h. The reaction mixture was cooled to roomtemperature and quenched with ice cold water. The aqueous layer wasneutralized with NH₄OH and the separated solid was fitered. It waswashed well with water and dried. The crude product obtained was takento next step without purification.

[0611] Brown solid; Yield: 10 g, 81%; M+H 248. mp 97° C.

[0612] Step 2: Imidazo[2,1-b]-benzthiazole-2-methanol:

[0613] To a stirred slurry of LiAlH₄ (2.0 g, excess) in dry THF, ethylimidazo[2,1-b]-benzthiazole-2-carboxylate (4.9 g, 20 mmol) was slowlyadded in THF (100 ml) at 0° C. After the addition, the reaction mixturewas stirred at room temperature for 1 h and quenched with saturatedNH₄Cl/NH₄OH. The separated solid was diluted with Chloroform/MeOH (3:1)and filtered through a pad of celite. The organic layer was washed oncewith saturated NaCl and dried over anhydrous MgSO₄. It was filtered andconcentrated. The brown solid obtained was taken to next step with outpurification. Yield: 3.8 g, 93%; M+H 205; mp 131° C.

[0614] Step 3: 2-Formyl-Imidazo[2,1-b]-benzthiazole:

[0615] To a stirred solution of imidazo[2,1-b]-benzthiazole-2-methanol(2.04 g, 10 mmol) in methylene chloride (200 ml), activated MnO₂ (15 g,excess) was added. The reaction mixture was stirred at room temperaturefor 24 h and filtered through a pad of celite. The reaction mixture wasconcentrated and the product was purified by silica gel columnchromatography by eluting it with 75% ethyl acetate; hexane. Brownsolid; Yield: 800 mg, 40%; M+H 203.

[0616] Step 4: 4-Nitrobenzyl-6-[(acetyloxy)(imidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:2-Formyl-Imidazo[2,1-b]-benzthiazole (444 mg, 2.2 mmol) and a dry THFsolution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (772 mg, 2 mmol) were added successively to adry acetonitrile (15 mL) solution of anhydrous MgBr₂:etherate (619 mg2.4 mmol) under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to a silicagel column, then the column was eluted with ethyl acetate:hexane (1:1).Collected fractions were concentrated under reduced pressure and themixture of diastereoisomers were taken to the next step. Pale yellowamorphous solid; Yield: 850 mg, 67%; mp 69° C.; M+H 630

[0617] Step 5:(5R),(6Z)-6-(Imidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid:

[0618] 4-Nitrobenzyl-6-[(acetyloxy)(imidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(500 mg, 0.79 mmol) was dissolved in THF (17 mL) and acetonitrile (36mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 1 N NaOH was added to adjust the pH to 8.5. The filtrate waswashed with ethyl acetate and the aqueous layer was separated. Theaqueous layer was concentrated under high vacuum at 35° C. to give ayellow precipitate. The precipitate was dissolved in acetonitrile andloaded on a HP-21 reverse phase column. It was eluted with deionizedwater (2 L) and latter eluted with 10% acetonitrile:water. Yield: 105mg, 35%; as yellow crystals; mp 233° C.; M+H 356.

[0619]¹H NMR (DMSO-d₆) δ 6.51 (s, 1H), 6.53 (s, 1H), 7.09 (s, 1H), 7.47(t, 1H, J=7.5 Hz), 7.54 (t, 1H, J=7.5 Hz), 8,06 (t, 1H), 8.62 (s, 1H).

Example 2 Preparation of(5R,6Z)-6-[(7-methoxyimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0620] Step 1: Ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate:

[0621] Ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate wasprepared according to the procedure as outlined in Example 1, (Step 1).Starting from 6-methoxy-2-amino benzothiazole (27 g, 0.15 mol) and ethylbromopyruvate (39.9 g, 0.2 mol), 24 g (43% Yield) of ethyl7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as abrown solid. (M+H) 277.

[0622] Step 2: 7-methoxy imidazo[2,1-b]-benzthiazole-2-methanol:

[0623] 7-methoxy imidazo[2,1-b]-benzthiazole-2-methanol was preparedaccording to the procedure outlined in Example 1, (Step 2). Startingfrom ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate (12.5 g,43.5 mmol) and LiAlH₄ solution (43.5 ml, 0.5 M solution in THF), 4.0 g(40% yield) of the alcohol derivative was isolated as a brown solid.(M+H) 235.

[0624] Step 3: 2-Formyl-7-methoxyimidazo[2,1-b]-benzthiazole:

[0625] 2-Formyl-7-methoxyimidazo[2,1-b]-benzthiazole was preparedaccording to the procedure outlined in Example 1, (Step 3). Startingfrom 7-methoxy imidazo[2,1-b]-benzthiazole-2-methanol (4.0 g 17 mmol) inmethylene chloride/DMF(300 mL: 50 mL) and active MnO₂ (12 g, excess),822 mg (21% Yield) of the aldehyde derivative was isolated as brownsolid. (M+H) 233.

[0626] Step 4: 4-Nitrobenzyl-6-[(acetyloxy)(7-methoxyimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0627] 2-Formyl-7-methoxyimidazo[2,1-b]-benzthiazole (822 mg, 3.5 mmol)and the dry THF solution (40 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.364, 3.54 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂:etherate (1.3g, 5 mmol) under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to a silicagel column, then the column was eluted with ethyl acetate:hexane (1:1).Collected fractions were concentrated under reduced pressure and themixture of diastereoisomers were taken to next step. Pale yellowamorphous solid; Yield: 2.24 g, 95%; M+H 660.

[0628] Step 5:(5R),(6Z)-6-[(7-methoxyimidazor[0.2-b][1,3]benzothiazol-2-ylmethylene)]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid:

[0629] 4-Nitrobenzyl-6-[(acetyloxy)(7-methoxyimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(659 mg, 1.0 mmol) was dissolved in THF (17 mL) and acetonitrile (36mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 1 N NaOH was added to adjust pH to 8.5. The filtrate was washedwith ethyl acetate and the aqueous layer was separated. The aqueouslayer was concentrated under high vacuum at 35° C. to give yellowprecipitate. The precipitate was filtered and washed with H₂O, MeCN,acetone to give the title compound. Yield: 68 mg, 23%; as yellowcrystals; mp 284; M+H 386.

[0630]¹H NMR (DMSO-d₆) δ 3.89 (s, 3H), 6.58 (s, 1H), 6.64 (s, 1H), 7.14(s, 1H), 7.2 (dd, 1H, J=6.0 Hz), 7.75 (d, 1H, J=3.0 Hz), 8,03 (d, J=6.0Hz 1H), 8.62 (s, 1H).

Example 3 Preparation of(5R,6Z)-6-[(7-chloroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0631] Step 1: Ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate:

[0632] Ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate wasprepared according to the procedure as outlined in Example 1, (Step 1).Starting from 6-chloro-2-amino benzothiazole (9.2 g, 50 mmol) and ethylbromopyruvate (11.6 g, 60 mmol), 8.5 g (60% Yield) of ethyl7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as brownsolid. (M+H) 281.

[0633] Step 2: 7-chloroimidazo[2,1-b]-benzthiazole-2-methanol:

[0634] 7-chloro imidazo[2,1-b]-benzthiazole-2-methanol was preparedaccording to the procedure outlined in Example 1, (Step 2). Startingfrom ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate (9.0 g,32.1 mmol) and LiAlH₄ (4.0 g, excess), 5.5 g (72% yield) of the alcoholderivative was isolated as brown solid. mp 166° C. (M+H) 239.

[0635] Step 3: 2-Formyl-7-chloroimidazo[2,1-b]-benzthiazole:

[0636] 2-Formyl-7-chloroimidazo[2,1-b]-benzthiazole was preparedaccording to the procedure outlined in Example 1, (Step 3). Startingfrom 7-chloroimidazo[2,1-b]-benzthiazole-2-methanol (4.0 g 16.8 mmol) inmethylene chloride/MeOH (300 mL: 50 mL) and active MnO₂ (20 g, excess),2.2 g (55% yield) of the aldehyde derivative was isolated as brownsolid. (M+H) 236.

[0637] Step 4: 4-Nitrobenzyl-6-[(acetyloxy)(7-chloroimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0638] 2-Formyl-7-chloroimidazo[2,1-b]-benzthiazole (270 mg, 1.14 mmol)and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (500 mg, 1.14 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (390mg, 1.5 mmol)under an argon atmosphere at room temperature. Aftercooling to −20° C., Et₃N (2.0 mL) was added in one portion. The reactionvessel was covered with foil to exclude light. The reaction mixture wasstirred for 2 h at −20° C. and treated with acetic anhydride (1.04 mL)in one portion. The reaction mixture was warmed to 0° C. and stirred for15 h at 0° C. The mixture was diluted with ethyl acetate and washed with5% citric acid aqueous solution, saturated sodium hydrogen carbonate,and brine. The organic layer was dried (MgSO₄) and filtered through apad of Celite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 495 mg, 65%; M+H 665.

[0639] Step 5:(5R),(6Z)-6-[(7-chloroimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid:

[0640]4-Nitrobenzyl-6-[(acetyloxy)(7-chloroimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(450 mg, 0.67 mmol) was dissolved in THF (20 mL) and acetonitrile (10mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate waswashed with ethyl acetate and the aqueous layer was separated. Theaqueous layer was concentrated under high vacuum at 35° C. to give ayellow precipitate. The product was purified by HP21 resin reverse phasecolumn chromatography. Initially the column was eluted with deionizedwater (2 L) and latter with 10% acetonitrile:water. The fractionscontaining the product were collected and concentrated under reducedpressure at room temperature. The yellow solid was washed with acetone,filtered and dried. Yield: 80 mg, 18%; as yellow crystals; mp 240° C.;(M+H+Na) 412.

[0641]¹H NMR (DMSO-d₆) δ 6.6 (s, 2H), 7.1 (s, 1H), 7.62 (dd, 1H), 8.11(d, 1H), 8.2 (s, 1H), 8.6 (s, 1H).

Example 4 Preparation of(5R),(6Z)-6-Imidazo[1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0642] Imidazo[1,2-a]quinoline-2-carbaldehyde

[0643] Imidazo[1,2-a]quinoline-2-carbaldehyde was prepared by the methodof Westwood and co-workers (J. Med. Chem. 1988, 31,1098-1115).

[0644] Step 1: (5R,6RS)-6-[(RS)-Acetoxyimidazo[1,2-a]quinolin-2-ylmethyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitrobenzyl Ester:

[0645] Imidazo[1,2-a]quinoline-2-carbaldehyde (1.09 g) and a dry THFsolution (75.5 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (2.22 g) were added successively to a dryacetonitrile (75.5 mL) solution of anhydrous MgBr₂ (2.5 g) under anargon atmosphere at room temperature. After cooling to −20° C., Et₃N(1.85 mL) was added in one portion. The reaction vessel was covered withfoil to exclude light. The reaction mixture was stirred for 2 h at −20°C. and treated with acetic anhydride (1.04 mL) in one portion. Thereaction mixture was warmed to 0° C. and stirred for 15 h at 0° C. Themixture was diluted with ethyl acetate and washed with 5% citric acidaqueous solution, saturated sodium hydrogen carbonate, and brine. Theorganic layer was dried (MgSO₄) and filtered through a pad of Celite.The pad was washed with ethyl acetate. The filtrate was concentratedunder reduced pressure. The residue was applied to a silica gel column,then the column was eluted with CHCl₃-acetone(1/0˜95/5). Collectedfractions were concentrated under reduced pressure followed byrecrystallization from CHCl₃-Et₂O to give the title compound as oneisomer. (pale yellow crystals, yield: 1.3 g, 38%).

[0646]¹H NMR (CDCl₃) δ 2.37 (s, 3H), 5.29 (d, 1H, J=13.5 Hz), 5.45 (d,1H, J=13.5 Hz), 6.22 (s, 1H), 7.14 (s, 1H), 7.46-7.52 (m, 3H), 7.56 (d,1H, J=9.6 Hz), 7.62 (d, 2H, J=8.6 Hz), 7.64-7.69 (m, 1H), 7.83 (dd, 1H,J=1.1, 7.9 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.99 (s, 1H), 8.25 (d, 2H, J=8.6Hz).

[0647] Step 2:(5R),(6Z)-6-Imidazor[1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid:

[0648](5R,6RS)-6-[(RS)-Acetoxyimidazo[1,2-a]quinolin-2-ylmethyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitrobenzyl ester (1.3 g) was dissolved in THF (17 mL) andacetonitrile (36 mL). Freshly activated Zn dust (5.2 g) was addedrapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The reaction vesselwas covered with foil to exclude light. The reaction mixture wasvigorously stirred for 2 h at room temperature. The reaction mixture wasfiltered, cooled to 3° C., and 1 N NaOH was added to adjust the pH to8.5. The filtrate was washed with ethyl acetate and the aqueous layerwas separated. The aqueous layer was concentrated under high vacuum at35° C. to give a yellow precipitate. The precipitate was filtered andwashed with H₂O, acetonitrile, and acetone to give the title compound,yield 297 mg, 38%, as yellow crystals mp 205° C.

[0649]¹H NMR (D₂O) d 6.19 (s, 1H), 6.36 (s, 1H), 6.87 (s, 1H), 6.96 (d,1H, J=9.5 Hz), 7.32 (d, 1H, J=9.5 Hz), 7.33 (s, 1H), 7.44˜7.57 m, 4H).

Example 5 Preparation of(5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[dlimidazo[2,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0650] Step 1: Preparation of ethyl6.7-dihydro-5H-cyclopentardlimidazo[2.1-b][1,3]thiazole-2-carboxylate.

[0651] A mixture of 2-chlorocyclopentanone (11.8 g, 100 mmol) andthiourea (8.0 g 101 mmol) was refluxed in ethanol: THF (1:2) for 16 hrs.The reaction mixture was cooled to room temperature and the separatedwhite solid was filtered. (9.0 g separated) This was dissolved inanhydrous ethanol (100 ml) and sodium methoxide (2.7 g, 51 mmol). Tothis ethyl bromopyruvate (10.0 g) was added and stirred at roomtemperature for 2 hrs. Then it was refluxed for 48 hrs. At the endreaction mixture was cooled to room temperature and concentrated. Theresidue was extracted with chloroform and washed well with water. Theproduct was purified by silica-gel column chromatography by eluting itwith 50% ethyl acetae: hexane. Red semi-solid; Yield: 3.0 g; M+H 237.

[0652] The ester was reduced with LiAlH₄ and the resultant alcohol wasoxidized with active MnO₂. The aldehyde obtained was taken to next step.

[0653] Step 3: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)(6.7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-yl)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0654] 2-Formyl-6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazole(600 mg, 3.1 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.2 g, 3 mmol) were added successively to thedry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.2 g, 3.0mmol)under an argon atmosphere at room temperature. After cooling to−20° C., Et₃N (2.0 mL) was added in one portion. The reaction vessel wascovered with foil to exclude light. The reaction mixture was stirred for2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 850 mg, 45%; M+H 620.

[0655] Step 4: Preparation of(5R),(6Z)-6-(6.7-dihydro-5H-cyclopentardlimidazo[2,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0656] 4-nitrobenzyl(5R)-6-[(acetyloxy)(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-yl)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(850 mg, 1.37 mmol) was dissolved in THF (20 mL) and acetonitrile (10mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate waswashed with ethyl acetate and the aqueous layer was separated. Theaqueous layer was concentrated under high vacuum at 35° C. to give ayellow precipitate. The product was purified by HP21 resin reverse phasecolumn chromatography. Initially the column was eluted with deionizedwater (2 L) and latter with 10% acetonitrile:water. The fractionscontaining the product were collected and concentrated under reducedpressure at room temperature. The yellow solid was washed with acetone,filtered and dried. Yield: 138 mg, 29%; as yellow crystals; mp 192° C.;(M+H+Na) 367. ¹H NMR (DMSO-d₆) δ 2.51 (m, 4H), 3.01 (m, 2H), 8.2 (s,1H), 7.1 (s, 1H), 6.55 (s, 1H), 6.4 (s, 1H).

Example 6 Preparation of(5R),(6Z)-6-(Imidazo[1.2-a]quinoxaline-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hepto-2-ene-2-carboxylicAcid, Sodium Salt

[0657] Imidazo[1,2-a]quinoxaline-2-carboxaldehyde

[0658] Imidazo[1,2-a]quinoxaline-2-carboxaldehyde was prepared by themethod of Westwood and co-workers (J. Med. Chem. 1998, 31, 1098-1115).

[0659] Step 1: (5R. 6RS)-6-((RS)-Acetoxyimidazo[1,2-a]quinoxalin-2-ylmethyl)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid p-nitrobenzyl Ester:

[0660] A dry acetonitrile (33 mL) solution ofimidazo[1,2-a]quinoxaline-2-carboxaldehyde (505 mg) was added to a dryacetonitrile (20 mL) solution of MgBr₂ (1.1 g) under an nitrogenatmosphere at room temperature, and the mixture was stirred for 10 min.After addition of the dry THF (25 mL) solution of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (931 mg), the mixture was cooled to −20° C.then triethylamine (0.8 mL) was added in one portion. The reactionvessel was covered with foil to exclude light. The reaction mixture wasstirred for 4 h at −20° C. and treated with 4,4-dimethylamino pyridine(58 mg) and acetic anhydride (0.44 mL) in one portion. The reactionmixture was warmed to 0° C. and stirred for 16 h at 0° C. 10% Citricacid aqueous solution (200 mL) was added to the reaction mixture and theaqueous layer was extracted with ethyl acetate (3×100 mL). The organiclayer was washed with water, saturated sodium hydrogen carbonate andbrine, dried (MgSO₄) and filtered. The filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂— acetone (50:1), and the titlecompound was obtained as a diastereomeric mixture (78:22, pale brownfoamy amorphous, 1.0 g, 68.9%).

[0661]¹H NMR (CDCl₃) δ 2.07 (s, 0.66H), 2.38 (s, 2.34H), 5.30 (d, 1H,J=13.5 Hz), 5.45 (d, 0.78H, J=13.5 Hz), 5.48 (d, 0.22H, J=13.5 Hz), 6.24(s, 0.78H), 6.46 (s, 0.22H), 6.63 (s, 0.22H), 7.18 (s, 0.78H), 7.50 (s,0.78H), 7.52 (s, 0.22H), 7.61 (d, 1.56H, J=8.7 Hz), 7.63 (d, 0.44H,J=8.8 Hz), 7.64-7.67 (m, 1H), 7.68-7.73 (m, 1H), 7.92-7.95 (m, 1H), 8.08(s, 0.78H), 8.13-8.16 (m, 1H), 8.24 (d, 1.56H, J=8.7 Hz), 8.25 (d,0.44H, J=8.8 Hz), 8.33 (s, 0.22H), 9.05 (s, 0.78H), 9.09 (s, 0.22H).

[0662] Step 2:(5R),(6Z)-6-(Imidazo[1,2-a]quinoxaline-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hepto-2-ene-2-carboxylicAcid, Sodium Salt:

[0663] (5R, 6RS)-6-((RS)-Acetoxyimidazo[1,2-a]quinoxalin-2-ylmethyl)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester (951 mg) and 10%Pd—C (50% wet, 477 mg) were added to a mixture of THF (48 mL) and 0.5mol/L phosphate buffer (pH 6.5, 48 mL). The mixture was hydrogenated at400 kPa at room temperature for 4 h. The reaction solution was filteredand Pd—C was washed with water and n-butanol. The reaction mixture wascooled to 0° C. and 1 N NaOH was added to adjust the ph to 8.5. Theaqueous layer was separated and then the organic layer was extractedwith water. The combined aqueous layer was concentrated to 57 g andapplied to Diaion HP-21 resin (60 mL, Mitsubishi Kasei Co. Ltd.) columnchromatography. After adsorbing, the column was eluted with water andthen 5, 10, 15 and 20% acetonitrile:water solution (each 60 mL). Thecombined fractions were concentrated under high vacuum at 35° C. andlyophilized to give the title compound as a yellow amorphous solid,yield 148 mg (26.1%), mp 300° C. (dec). ¹H NMR (D₂O) δ 5.92 (s, 1H),6.23 (s, 1H), 6.66 (s, 1H), 7.11-7.22 (m, 3H), 7.25 (d, 1H, J=7.9 Hz),7.50 (s, 1H), 8.03 (s, 1H); IR (KBr) 3413, 1748, 1592, 1553 cm⁻¹;I^(max) (H₂O) 340, 293, 237, 218 nm.

Example 7 Preparation of(5R,6Z)-6-[(7-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0664] Step 1: Ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate:

[0665] Ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate wasprepared according to the procedure as outlined in Example 1, (Step 1).Starting from 6-methyl-2-amino benzothiazole (3.2 g, 20 mmol) and ethylbromopyruvate (4.0 g, 20.4 mmol), 3.0 g (57% Yield) of ethyl7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as brownsolid. (M+H) 261.

[0666] Step 2: 2-Formyl-7-methylimidazo[2,1-b]-benzthiazole:

[0667] To a stirred solution of Ethyl7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate (4.0 g, 15.38 mmol) indry THF at −78° C., DIBAL (1M. solution in toluene) (16.0 ml, 16 mmol)was added. The reaction mixture was stirred at −78° C. and slowlyelevated to room temperature. The reaction mixture was stirred at roomtemperature for 30 minutes and quenched with saturated NH₄Cl. Thereaction mixture was extracted with chloroform and washed well withwater. The organic layer was dried over anhydrous MgSO₄; filtered andconcentrated. The residue was purified bt SiO₂ column chromatography byeluting it with chloroform: metrhanol (20:1). Brown solid; (M+H) 217;Yield: 800 mg (24%)

[0668] Step 3: 4-Nitrobenzyl-6-[(acetyloxy)(7-methylimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0669] 2-Formyl-7-methylimidazo[2,1-b]-benzthiazole (432 mg, 2.0 mmol)and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (772 mg, 2.0 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (566mg, 2.0 mmol) under an argon atmosphere at room temperature. Aftercooling to −20° C., Et₃N (2.0 mL) was added in one portion. The reactionvessel was covered with foil to exclude light. The reaction mixture wasstirred for 2 h at −20° C. and treated with acetic anhydride (1.04 mL)in one portion. The reaction mixture was warmed to 0° C. and stirred for15 h at 0° C. The mixture was diluted with ethyl acetate and washed with5% citric acid aqueous solution, saturated sodium hydrogen carbonate,and brine. The organic layer was dried (MgSO₄) and filtered through apad of Celite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 400 mg, 31%; M+H 645.

[0670] Step 4:(5R),(6Z)-6-[(7-methylimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid:

[0671]4-Nitrobenzyl-6-[(acetyloxy)(7-methylimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(350 mg, 0.54 mmol) was dissolved in THF (20 mL) and acetonitrile (10mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate waswashed with ethyl acetate and the aqueous layer was separated. Theaqueous layer was concentrated under high vacuum at 35° C. to give ayellow precipitate. The product was purified by HP21 resin reverse phasecolumn chromatography. Initially the column was eluted with deionizedwater (2 L) and latter with 10% acetonitrile:water. The fractionscontaining the product were collected and concentrated under reducedpressure at room temperature. The yellow solid was washed with acetone,filtered and dried. Yield: 110 mg, 55%; as yellow crystals; mp 178° C.(Dec); (M+H+Na) 392.

[0672]¹H NMR (DMSO-d₆) δ 8.56 (s, 1H), 7.93 (d, 1H), 7.83 (s, 1H), 7.38(d, 1H), 7.07 (s, 1H), 6.51 (s, 2H), 2.42 (s, 3H).

[0673] Step 4:(5R),(6Z)-6-[(7-methylimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid: (Procedure B)

[0674]4-Nitrobenzyl-6-[(acetyloxy)(7-methylimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(350 mg, 0.54 mmol) was dissolved in THF (40 mL) and 6.5 pH phosphatebuffer (40 ml) and hydrogenated over Pd/C (10%, 200 mg) at 40 psipressure for 3 hrs at room temperature. At the end, reaction mixture wasfiltered through a pad of celite and washed with acetonitrile. Thereaction mixture was concentrated to 40 ml and cooled to 0° C. and pHwas adjusted to 8.5 by adding 1 N NaOH. The product was directly loadedover HP21 resin reverse phase column chromatography. Initially thecolumn was eluted with deionized water (2 L) and latter with 10%acetonitrile:water. The fractions were concentarated and the yellowsolid was washed with acetone, filtered and dried. Yield: 110 mg, 55% asyellow solid.

Example 8 Preparation of (5R),(6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid Sodium Salt

[0675] Step 1:5,6,7,8-Tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine

[0676] The 12.7% solution of HCl in ethanol (5.35 mL) and 10% Pd—C (50%wet) (2.5 g) were added to the mixture of[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.5 g) in ethanol (72 mL). Thereaction mixture was hydrogenated at 400 KPa of H₂ for 3 days at roomtemperature. The mixture was filtered and concentrated under reducedpressure. The residue was treated with saturated potassium carbonatesolution and extracted with chloroform. The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure. The title compound wasobtained as a pale yellow solid (2.31 g, 90%). ¹H-NMR (400 MHz, CDCl₃) δ1.88-1.94 (m, 2H), 1.98-2.05 (m, 2H), 2.77 (t, 2H, J=6.2 Hz), 3.95 (t,2H, J=6.2 Hz), 4.09 (brs, 2H).

[0677] Step 2:4,5,6,7-Tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-carboxylicAcid Ethyl Ester

[0678] Ethyl bromopyruvate (10.23 g) was added to the mixture of5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (5.8 g) in1,2-dimethoxyethane (320 mL). The reaction mixture was stirred for 5hours at room temperature and concentrated to 100 mL under reducedpressure. The precipitate was obtained by an addition of diethyl ether(200 mL), followed by filtration. The precipitate was dissolved inethanol (175 mL) and stirred for 20 hours at 110° C. in shield tube. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The residue was treated with saturated potassiumcarbonate solution and extracted with chloroform. The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. The residue wasapplied to silica gel column chromatography, then eluted with ethylacetate—methanol (1/1). The title compound was obtained as a pale yellowsolid (7.56 g, 77%). ¹H-NMR (400 MHz, CDCl₃) δ 1.42 (t, 3H, J=7.1 Hz),2.14-2.25 (m, 4H), 3.11 (t, 2H, J=6.1 Hz), 4.37 (t, 2H, J=5.7 Hz), 4.41(q, 2H, J=7.1 Hz), 7.57 (s, 1H).

[0679] Step 3:4,5,6,7-Tetrahydro-1.3a,3b,8-tetraaza-cyclopenta[a]indene-2-carbaldehyde

[0680] 1.01 M Diisobutylalminium hydride in toluene (1.06 mL) was addeddropwise to the solution of4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-carboxylicacid ethyl ester (100 mg) in dry THF (5 mL) at −78° C. under a nitrogenatmosphere. The reaction mixture was stirred for 30 minutes at −78° C.and treated with ethanol (ca. 1 mL). The mixture was warmed to 0° C. andstirred for 1 h at 0° C. The reaction solution was diluted with ethylacetate (20 mL), treated with 0.5 mL saturated ammonium chloridesolution, and sonicated for ca. 5 minutes (until a precipitate wasdeposited enough). The mixture was dried (Na₂SO₄) and filtered through apad of Celite. The filtrate was concentrated under reduced pressure. Theresidue was crystallized from dichloromethane and diethyl ether to givethe title compound (47.4 mg, 58%). ¹H-NMR (400 MHz, CDCl₃) δ 2.16-2.27(m, 4H), 3.14 (t, 2H, J=6.1 Hz), 4.39 (t, 2H, J=5.7 Hz), 7.53 (s, 1H),10.01 (s, 1H).

[0681] Step 4: (5R,6RS)-6-{(RS)-Acetoxy-[4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-yl]-methyl}-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid 4-nitro-benzyl Ester

[0682]4,5,6,7-Tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-carbaldehyde(2.97 g) was added to the dry acetonitrile (110 mL) solution ofanhydrous MgBr₂ (4.45 g) under a nitrogen atmosphere at roomtemperature. The dry THF solution (110 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (2.97 g) was added to the reaction mixture,cooled to −20° C., and triethylamine (6.45 mL) was added in one portion.The reaction vessel was covered with foil to exclude light. After themixture was stirred for 1.2 h at −20° C., acetic anhydride (2.9 mL) wasadded in one portion. The reaction mixture was warmed to 0° C. andstirred for 16.5 h at 0° C. The mixture was diluted with ethyl acetateand washed with H₂O and brine. The organic layer was dried (MgSO₄) andfiltered through a pad of Celite. The pad was washed with ethyl acetate.The filtrate was concentrated under reduced pressure. The residue wasapplied to silica gel column chromatography, eluted with ethylacetate—n-hexane (3/1) and then with ethyl acetate—methanol (5/1). Thetitle compound was obtained as a brown amorphous solid (651.6 mg, 13%).¹H-NMR (400 MHz, CDCl₃) δ 2.10-2.24 (m, 4H), 2.29 (s, 3H), 3.04-3.07 (m,2H), 4.28-4.32 (m, 2H), 5.27 (d, 1H, J=13.7 Hz), 5.43 (d, 1H, J=13.7Hz), 6.19 (s, 1H), 6.91 (s, 1H), 7.01 (s, 1H), 7.49 (s, 1H), 7.59-7.62(m, 2H), 8.23-8.25 (m, 2H).

[0683] Step 5: (5R),(6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid Sodium Salt

[0684] (5R,6RS)-6-{(RS)-Acetoxy-[4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-yl]-methyl}-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (643.6 mg) was dissolved in THF (9 mL) andacetonitrile (4.2 mL). Freshly activated Zn dust (2.57 g) and 0.5 Mphosphate buffer (pH 6.4, 13.2 mL) were added to the reaction mixture.The reaction vessel was covered with foil to exclude light. The mixturewas vigorously stirred for 2 h at room temperature. The mixture wascooled to 3° C., and 1 N NaOH aqueous solution was added to adjust pH to7.5. The reaction solution was mixed with ethyl acetate and filteredthrough a pad of Celite. The pad was washed with water. The aqueouslayer was concentrated to 20 mL under high vacuum at 35° C. Theconcentrate was applied to Diaion HP-21 (60 mL, Mitsubishi Kasei Co.Ltd.) resin column chromatography. After adsorbing, the column waseluted with water and then with 2.5-10% acetonitrile-water. The combinedfractions was concentrated under high vacuum at 35° C. and lyophilizedto give the title compound as a yellow amorphous solid (68 mg, 18%, pH7.4). Mp 175° C. (dec); ¹H-NMR (400 MHz, D₂O) δ 1.85-2.03 (m, 4H),2.85-2.99 (m, 2H), 4.07-4.14 (m, 2H), 6.34 (s, 1H), 6.74 (s, 1H), 6.76(s, 1H), 7.28 (s, 1H).

Example 9 Preparation of (5R,6E)-6-[(10-benzyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-8-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0685] Step 1: Preparation of8-(hydroxymethyl)dibenzo[b,f][1,4]oxazepin-[(10H)-one.

[0686] Lithium aluminum hydride (11 mL, 11 mmole) was slowly added tothe solution of11-Oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepine-8-carboxylic acid methylester (1.346 g, 5 mmole) in THF under N₂ at room temperature. Thereaction mixture was stirred for 1 hour and 45 minutes then quenchedwith 2N of HCl until the pH value reaches 2-3. Removed all the THF byrotary evaporation, and extracted the reaction mixture with ethylacetate for five times, dried the organic layer with sodium sulfate andfiltered and concentrated. Obtained the desired compound (white solid)in 46% yield.

[0687] Step 2: Preparation of11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carbaldehyde.

[0688] 8-(hydroxymethyl)dibenzo[b,f][1,4]oxazepin-11 (10H)-one (0.241 g,1 mmole) in acetonitrile was added to the molecular sieves (1 g) underN₂ at room temperature then 4-methylmorpholine N-oxide (0.175 g, 1.5mmole) was also added into the reaction mixture. After stirring themixture for 10 minutes, tetrapropylammonium perruthenate (0.0176 g, 0.05mmole) was added and the reaction followed by t.l.c. until complete.Dilute the reaction mixture with 10 ml of ethyl acetate and flashed itthrough a small silica gel column. Collected all the ethyl acetate thatcontains desired material, extracted the organic layer with 1 N HCl andalso washed it with brine. Dried the organic layer over sodium sulfateand filtered and concentrated. Obtained the desired-compound (whitesolid) in 83% yield.

[0689] Step 3: Preparation of10-benzyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepine-8-carbaldehyde:

[0690] Potassium carbonate anhydrous (0.207 g, 1.5 mmole) and benzylbromide (0.205 g, 1.2 mmole) were added to a solution of the11-oxo-10,11 dihydrodibenzo[b,f][1,4]oxazepine-8-carbaldehyde (0.240 g,1 mmole) in acetonitrile under N₂ at room temperature. The reactionmixture then was refluxed for 4 hours, and cooled to room temperature.Diluted the reaction mixture with ethyl acetate and filtered through amagnesol pad and concentrated. Purified with silica gel column and 50%ethyl acetate in hexane. Obtained the desired compound (light yellowoil) in 63% yield.

[0691] Step 4: Preparation of6-[acetoxy-(10-benzyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-8-yl)-methyl]-6-bromo-7oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester;

[0692]10-benzyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepine-8-carbaldehyde(0.250 g, 0.759 mmole) in acetonitrile was added to magnesium bromide(0.419 g, 2.28 mmole) under N₂ at room temperature. The dry THF solutionof(5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitrobenzyl ester (0.292 g, 0.758 mmole) then was added to themixture. After 15 minutes the reaction mixture was cooled to −20° C.,and triethylamine (0.317 mL, 2.27 mmole) was added. The reaction flaskwas covered with foil to exclude light. After 4 hours at −20° C.,treated with acetic anhydride (0.358 mL, 3.795 mmole) and DMAP (0.00927g, 0.0759 mmole). Warmed up the reaction mixture to 0° C. and placed itin freezer overnight. Reaction solution was concentrated and dissolvedwith ethyl acetate and washed with 5% of citric acid aqueous solution,saturated NaHCO₃, water and brine. Organic layer was dried in sodiumsulfate and filtered and concentrated. Purified with silica gel columnand 1:15 ethyl acetate/CH₂Cl₂. Obtained the desired compound (lightyellow oil) in 41% yield.

[0693] Step 5: Preparation of6-(10-benzyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-8-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt:

[0694] A 0.5M phosphate buffer solution (pH 6.5) was added to a solutionof6-[acetoxy-(10-benzyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-8-yl)-methyl]-6-bromo-7oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (0.210 g, 0.273 mmole) in THF, followed by 10%Pd—C (0.0546 g). The reaction mixture then was hydrogenated at 40 psifor three hours. Filtered through a celite pad and removed the THF byrotary evaporation, extracted the mixture with ethyl acetate and washedwith water and brine. Dried the organic layer with sodium sulfate andfiltered and concentrated. Dissolved the NaHCO₃ with minimal amount ofdistal water and added it to the reaction mixture along with a smallamount of ethyl acetate until the pH value reaches 7-8, evaporated theethyl acetate. Purified with reverse phase column (MCI Gel CHP20P) withvarying amounts of acetonitrile (0%-20%) in water. Removed theacetonitrile and water by rotary evaporation, and freeze-dried thecompound. Obtained the desired material (yellow solid) in 24% yield.Mp:179° C. ¹H NMR (DMSO) δ 1.755-1.825 (s, 1H), 2.497-2.506 (d, 2H),5.243-5.434 (m, 2H), 6.516-6.770 (m, 1H), 7.039-7.792 (m, 11H).

Example 10 Preparation of6-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0695] Step 1: Preparation of4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine (S M: Ross, L. O.;Goodman, L.; Baker, B. R. J. Am. Chem. Soc. 1959, 81, 3108)

[0696] 5.1 grams of4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in200 ml xylene and 30 ml absolute ethanol. Then 6.8 gram for sodiumethoxide was added and the mixture was refluxed for 3 hours. Then thesolvent was removed in vacuo and 100 ml water was added to the residue.Filter and wash the cake with water (50 ml). The solid was furthervacuumed to dry for several hours. The desired product weighed 5.3 gram(98% yield). Mp: 133.8˜134.9° C.

[0697]¹H-NMR: (300 MHz, CDCl₃) δ. 6.23 (s, NH2), 4.28 (quartet, 2H,J=6.9 Hz), 2.6 (m, 2H), 1.93 (m, 2H), 1.27 (t, CH3, J=6.9 Hz); MS: 180.0(M+H)

[0698] Step 2: Preparation of5-Ethoxy-7,8-dihydro-6H-3.4.8b-triaza-as-indacene-2-carboxylic AcidEthyl Ester

[0699] 5.2 gram (29 mmol)4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in100 ml dry THF. Bromopyruvate (5.4 ml,) was then added dropwise with infive minutes. The mixture was stirred at 23° C. for one hour. It wasthen filtered and washed with ether to give 8.7 gram of solid. Thissolid was then dissolved in 50 ml ethanol and refluxed for two hours.The reaction mixture was cooled to room temperature and partitionedbetween 350 ml chloroform and 200 ml saturated sodium bicarbonate. Theorganic layer was separated and dried over magnesium sulfate. Filter offthe drying agent and concentrate to give 6.5 gram of product.

[0700] MP: 168.6˜168.7° C.

[0701]¹H-NMR: (300 MHz, CDCl₃) δ. 7.69 (s, 1H), 4.50 (qartet, 2H, J=7.2Hz), 4.40 (qartet, 2H, J=7.2 Hz), 3.11 (t, 2H, J=9.6 Hz), 2.88 (t, 2H,J=9.6 Hz), 2.88 (m, 2H), 1.43 (t, 2H, J=7.2 Hz).; MS: 276.2 (M+H)

[0702] Step 3: Preparation of5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carbaldehyde

[0703] 1.925 grams5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carboxylic acidethyl ester was dissolved in 40 ml dichloromethane and then cooled to−78° C. DIBAL (1 M, 21 ml, 3 eq.) was then added within five minutes.The reaction media was then quenched with 2 ml ethanol and partitionedbetween 350 ml dichloromethane and 100 ml 1 N sodium hydroxide. Theaqueous layer was washed with another 150 ml chloroform and the combinedorganic layer was dried over magnesium sulfate and filtered andconcentrated to give the corresponding alcohol. The alcohol is thendissolved in 150 ml dichloromethane and 10 grams of manganese dioxide isthen added. The mixture was stirred at 23° C. for two hours. Thereaction mixture was then filtered through a pad of celite andconcentrated to give 1.1 gram (68%) of the desired aldehyde.

[0704] MP: 237.2˜237.3° C.

[0705]¹H-NMR: (300 MHz, CDCl₃) δ. 9.94 (s, 1H, CHO), 8.39 (s, 1H), 4.46(quartet, 2H, J=7.2 Hz), 3.2 (m, 2H, CH2), 2.85 (m, 2H, CH2), 2.24 (m,2H, CH2), 1.38 (t, 3H, CH3, J=7.2 Hz); MS: 232.1 (M+H)

[0706] Step 4: Preparation of6-[acetoxy-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid 4-nitro-benzyl Ester

[0707] A 30 ml acetonitrile solution of5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carbaldehyde (693mg, 3 mmol) was added 1.03 gram of magnesium bromide etherate. Themixture was stirred at 23° C. for half an hour. Then a 30 ml dry THFsolution of the6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid4-nitro-benzyl ester (1.155 gram, 1 eq.) was injected within a minuteand the reaction mixture was then cooled to −20° C. Triethylamine (0.7ml, eq.) was then injected and the reaction mixture was stirred for fivehours at −20° C. Then acetic anhydride (0.377 ml, eq.) was injected andthe reaction mixture was left at zero degree for 18 hours. The reactionmedia was then diluted with 400 ml ethyl acetate and washed with 100 ml5% citric acid, 100 ml saturated sodium bicarbonate, and 100 ml brine.The organic layer was then dried over magnesium sulfate, filtered andconcentrated. Flash column chromatography using 20% ethyl acetate inhexane gave 1.1 gram product.

[0708] MP: 118.7˜119.1° C.

[0709]¹H-NMR: (300 MHz, CDCl₃) δ. 8.35 (d, 2H, J=11 Hz), 7.63 (m, 2H),7.41 (d, 1H, J=6.9 Hz), 7.08 (d, 1H, J=11 Hz), 6.47 (s, 1H), 5.55 (4H,CH2), 4.54 (m, 2H), 3.09 (m, 2H), 2.93 (m, 2H), 2.32 (m, 2H), 1.41 (t,J=9.6 Hz); MS: 660.1 (M+H)

[0710] Step 5: Preparation of6-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0711]6-[acetoxy-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.03 gram, 1.565 mmol) was suspended in 20 mlTHF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was thensubjected to 45 psi hydrogen for two hours. Then it was filtered througha pad of celite and concentrated in vacuo to remove most of the THF. Thesolution was then cooled to zero degree and basified to pH=8 with 1 Nsodium hydroxide. Then it was purified via reverse phase HPLC using 1liter of water followed by 5%˜25% acetonitrile and water. Water was thenremoved through concentrate in vacuo and 100 mg of product wascollected.

[0712] MP: >250° C.

[0713]¹H-NMR: (300 MHz, CDCl₃) δ. 7.52 (s, 1H), 6.95 (s, 1H), 6.54 (s,1H), 4.73 (m, 2H), 3.06 (m, 2H), 2.84 (m, 2H), 2.27 (m, 2H), 1.43 (t,3H); MS: 383.2 (M+H).

Example 11(5R,6E&Z)-7-oxo-6-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0714] Step 1: Preparation of1-(2-fluorobenzyl)-1H-pyrazole-3,5-dicarboxylate

[0715] 2-fluorobenzyl bromide (2.0 ml, 16.58 mmol) was added to amixture of diethyl 3,5-pyrazoledicarboxylate (3.01 g, 14.18 mmol),Cs₂CO₃ (5.57 g, 17.1 mmol), and acetonitrile (140 ml) under N₂. Heatedto 60° C. for two hours and then cooled to room temperature. Filteredand concentrated the reaction solution. Added water (˜200 mL) to theresulting residue and extracted with EtOAc. Washed organics with waterand brine. Dried organics over sodium sulfate and filtered andconcentrated. Obtained diethyl1-(2-fluorobenzyl)-1H-pyrazole-3,5-dicarboxylate (light-yellow oil) inquantitative yield.

[0716] Step 2: Preparation of1-(2-fluorobenzyl)-1H-pyrazole-3.5-methanediol

[0717] A 1M solution of DIBAL-H in THF (90 ml, 90 mmol) was added to asolution of diethyl 1-(2-fluorobenzyl)-1H-pyrazole-3,5-dicarboxylate(4.80 g, 14.99 mmol) in CH₂Cl₂ (90 ml) at 0° C. under N₂. After twohours quenched with NH₄Cl_((aq)) and suspension was formed. Filtered andextracted with EtOAc and washed with brine. Dried organics over sodiumsulfate and filtered and concentrated. Purified with silica gel columnand 5% MeOH in CH₂Cl₂. Obtained 3.4 g of the diol compound (clear oil)in 96% yield.

[0718] Step 3: Preparation of4H,10H-pyrazolo[5,1-c][1,4]benzoxazepine-2-carbaldehyde

[0719] The diol compound (3.83 g, 16.21 mmol) in HMPA (24 ml) was addedto a suspension of NaH (60%, 1.34 g, 33.5 mmol) in toluene (330 ml)under N₂. Rapidly heated to 95° C. for three hours and cooled to roomtemperature. Quenched with water and extracted with EtOAc. Washedorganics with water and brine. Dried organics over sodium sulfate andfiltered and concentrated. Purified with silica gel column and 2% MeOHin CH₂Cl₂. Obtained 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethanol(white solid). Yield: 0.71 g 20%.4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethanol (0.71 g, 3.28mmol), 4-methylmorpholine N-oxide (1/198 g, 10.23 mmol), molecularsieves (powder, 4 angstroms) (3.32 g), and acetonitrile (0.07M) wereplaced together under N₂. Tetrapropylammoniumperruthenate (0.113 g,0.322 mmol) was added and after three hours the reaction solution wasfiltered through celite and concentrated. Purified with silica gelcolumn and 1:1 EtOAc/Hexane. Obtained 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepine-2-carbaldehyde (white solid).Yield: 0.31 g 44%.

[0720] Step 4: Preparation of Preparation of6-[acetoxy-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepine-8-yl)-methyl]-6-bromo-7oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl Ester;

[0721] 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepine-2-carbaldehyde (0.19 g,0.887 mmol) in acetonitrile (14 ml) was added to MgBr₂ (0.49 g, 2.66mmol) under N₂. After 25 minutes6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid4-nitro-benzyl ester (0.342 g, 0.888 mmol.) in THF (14 ml) was added.After 15 minutes the reaction was cooled to −20° C. Ten minutes lateradded Et₃N (3eq) and placed reaction in the dark. After 6.5 hours addedAc₂O (0.42 ml, 4.45 mmol) and DMAP (0.011 g, 0.0900 mmol). Warmed to 0°C. and placed in freezer overnight. Reaction solution was concentratedand resulting residue was taken up in EtOAc. Washed with 5% citricacid_((aq)) and saturated NaHCO_(3(aq)). Further washed with water andbrine. Dried organics over sodium sulfate and filtered and concentrated.Purified with silica gel prep plates and 1:2 EtOAc/Hexane. Obtained thecondensation product (yellow gum/solid). Yield: 0.31 g, 54% yield.

[0722] Step 5:(5R,6E&Z)-7-oxo-6-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt:

[0723] Step 6: A 0.5M phosphate buffer solution (pH 6.5) (18 mL) wasadded to a solution of the condensation product (5) (0.300 g, 0.468mmol) in THF (18 mL). The Pd on Carbon (0.102 g) was added and thereaction mixture was hydrogenated at 40 psi for two hours. Filteredthrough celite and removed THF by rotary evaporation. Extracted withEtOAc. Dried organics over sodium sulfate and filtered and concentrated.NaHCO₃ (0.08 g, 0.952 mmol) was dissolved in a minimal amount of waterand added to the concentrated organics along with a small amount ofEtOAc. Filtered and removed EtOAc by rotary evaporation. Purified withreverse phase column (MCI Gel CHP20P) and varying amounts ofacetonitrile (0% to 15%) in water. Removed the acetonitrile and most ofthe water from the collected fractions by rotary evaporation.Freeze-dried the rest to obtain 41 mg of(5R,6E)-7-oxo-6-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt (6) (yellow solid) in 22% yield. HPLC found the purityto be 77% and the E/Z isomer ratio to be 3:2. ¹H-NMR (6, DMSO-d₆) 5.366(m, 4H), 5.649 (m, 4H), 6.326 (t, 2H), 6.444 (s, 2H), 6.551 (s, 2H),6.640 (s, 2H), 6.810 (s, 2H), 6.974 (m, 2H), 7.249 (m, 2H), 7.355 (m,2H). m/z (M+H)390.0

Example 12 (5R),(6Z)-6-(5H-Imidazo[2,1-a]isoindol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid Sodium Salt

[0724] Step 1: Preparation of 5H-Imidazo[2,1-a]isoindole-2-carbaldehyde

[0725] The solution of 2-bromo-3-isopropoxy-propenal (4.97 g) in dryacetonitrile (3 mL) was added to the mixture of 3-amino-1H-isoindole(3.4 g) in dry acetonitrile (100 mL). The reaction mixture was stirredfor 3.25 h at room temperature. Then triethylamine (3.6 mL) was added tothe mixture and heated to reflux for 2 h. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and washed with 20% potassiumhydrogen carbonate. After filtration through a pad of Celite, theorganic layer was dried (MgSO₄) and concentrated under reduced pressure.The residue was applied to silica gel column chromatography, then elutedwith ethyl acetate—hexane (3/1˜4/1). The crude compound was crystallizedfrom ethyl acetate and n-hexane to give the title compound (1.04 g,22%). ¹H NMR (400 MHz, CDCl₃) δ 5.01 (s, 2H), 7.28-7.52 (m, 3H), 7.90(s, 1H), 7.91-7.93 (m, 1H), 9.92 (s, 1H).

[0726] Step 2: Preparation of (5R,6RS)-6-[(RS)-Acetoxy-(5H-imidazo[2,1-a]isoindol-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid 4-nitro-benzyl Ester:

[0727] 5H-Imidazo[2,1-a]isoindole-2-carbaldehyde (736.8 mg) was added tothe dry acetonitrile (50 mL) solution of anhydrous MgBr₂ (1.8 g) under anitrogen atmosphere at room temperature. The dry THF solution (50 mL) of(5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.55 g) was added to the reaction mixture,cooled to −20° C., and triethylamine (1.34 mL) was added in one portion.The reaction vessel was covered with foil to exclude light. The mixturewas stirred for 2 h at −20° C. and treated with acetic anhydride (0.76mL) in one portion. The reaction mixture was warmed to 0° C. and stirredfor 18 h at 0° C. The mixture was diluted with ethyl acetate and washedwith H₂O, saturated sodium hydrogen carbonate, and brine. The organiclayer was dried (MgSO₄) and filtered through a pad of Celite. The padwas washed with ethyl acetate. The filtrate was concentrated underreduced pressure. The residue was applied to silica gel columnchromatography, then eluted with ethyl acetate—hexane (2/3˜1/1). Thetitle compound was obtained as two diastereo mixture (5/1, a pale yellowamorphous solid, 1.8 g, 73%). ¹H NMR (400 MHz, CDCl₃) δ 2.02 (s,0.84×3H), 2.27 (s, 0.16×3H), 4.89-4.94 (m, 2H), 5.29 (d, 1H, J=13.6 Hz),5.47 (d, 1H, J=13.6 Hz), 6.18 (s, 0.16×1H), 6.40 (s, 0.84×1H), 6.42 (s,0.84×1H), 6.94 (d, 0.16×1H, J=0.9 Hz), 7.18 (d, 0.16×1H, J=0.7 Hz),7.35-7.48 (m, 3H), 7.51 (s, 0.84×1H), 7.60-7.64 (m, 2H), 7.79-7.83 (m,1H), 8.23-8.27 (m, 2H).

[0728] Step 3: (5R),(6Z)-6-(5H-Imidazo[2,1-a]isoindol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid Sodium Salt

[0729] (5R,6RS)-6-[(RS)-Acetoxy-(5H-imidazo[2,1-a]isoindol-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.5 g) was dissolved in THF (21 mL) andacetonitrile (9.8 mL). Freshly activated Zn dust (6 g) and 0.5 Mphosphate buffer (pH 6.4, 30.8 mL) were added to the reaction mixture.The reaction vessel was covered with foil to exclude light. The mixturewas vigorously stirred for 2 h at room temperature. The mixture wascooled to 9° C., and 1 M NaOH aqueous solution was added to adjust pH to7.5. The reaction solution was mixed with ethyl acetate and filteredthrough a pad of Celite. The pad was washed with water and the aqueouslayer was separated. The aqueous layer was concentrated to 25 mL underhigh vacuum at 35° C. The concentrate was applied to Diaion HP-21 (100mL, Mitsubishi Kasei Co. Ltd.) resin column chromatography. Afteradsorbing, the column was eluted with water and then with 5-15%acetonitrile-water. The combined fractions was concentrated under highvacuum at 35° C. and lyophilized to give the title compound as a yellowamorphous solid (527 mg, 58%). Mp 170° C. (dec); ¹H NMR (400 MHz, D₂O) δ4.62 (s, 2H), 6.27 (s, 1H), 6.56 (s, 1H), 6.78 (s, 1H), 7.22-7.31 (m,4H), 7.52 (d, 1H, J=6.7 Hz).

Example 13 Preparation of(5R,6Z)-6-[(5-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0730] Step 1: Ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate:

[0731] Ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate wasprepared according to the procedure as outlined in Example 1, (Step 1).Starting from 4-methly-2-amino benzothiazole (8.0 g, 48.7 m.mol) andethyl bromopyruvate (14.0 g, 71.7 mmol), 6.0 g (45% Yield) of ethyl5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as abrown solid. (M+H) 261.

[0732] Step 2: 5-methyl imidazo[2,1-b]-benzthiazole-2-methanol:

[0733] 5-methyl imidazo[2,1-b]-benzthiazole-2-methanol was preparedaccording to the procedure outlined in Example 1, (Step 2). Startingfrom ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate (5.2 g, 20mmol) and LiAlH₄ solution (22 ml, 0.5 M solution in THF), 3 g (69%yield) of the alcohol derivative was isolated as a brown solid. (M+H)219.

[0734] Step 3: 2-Formyl-5-methylimidazo[2,1-b]-benzthiazole:

[0735] 2-Formyl-5-methylimidazo[2,1-b]-benzthiazole was preparedaccording to the procedure outlined in Example 1, (Step 3). Startingfrom 5-methyl imidazo[2,1-b]-benzthiazole-2-methanol (2.0 g 9.1 mmol) inmethylene chloride/DMF(300 mL: 50 mL) and active MnO₂ (12 g, excess),700 mg (35% Yield) of the aldehyde derivative was isolated as brownsolid. (M+H) 217.

[0736] Step 4: 4-Nitrobenzyl-6-[(acetyloxy)(5-methylimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0737] 2-Formyl-5-methylimidazo[2,1-b]-benzthiazole (432 mg, 2.0 mmol)and the dry THF solution (40 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (770 mg, 2 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂:etherate (1.3g, 5 mmol) under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to a silicagel column, then the column was eluted with ethyl acetate:hexane (1:1).Collected fractions were concentrated under reduced pressure and themixture of diastereo isomers were taken to next step. Pale yellowamorphous solid; Yield: 270 mg, 20%; M+H 644.

[0738] Step 5:(5R),(6Z)-6-[(5-methylimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid:

[0739] 4-Nitrobenzyl-6-[(acetyloxy)(5-methylimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(400 mg, 0.62 mmol) was dissolved in THF (17 mL) and acetonitrile (36mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 1 N NaOH was added to adjust pH to 8.5. The filtrate was washedwith ethyl acetate and the aqueous layer was separated. The aqueouslayer was concentrated under high vacuum at 35° C. to give yellowprecipitate. The precipitate was filtered and washed with H₂O, MeCN,acetone to give the title compound. Yield: 60 mg, 24%; as yellowcrystals; mp 192; M+Na 392.

[0740]¹H NMR (DMSO-d₆) δ 2.1 (s, 3H), 6.53 (s, 2H), 7.1 (s, 1H),7.34-7.36 (m, 2H), 7.85 (m, 1H), 8,58 (s, 1H).

Example 14 Preparation of(5R,6Z)-6-[(7-fluoroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0741] Step 1: Ethyl 7-fluoroimidazo[2,1-b]-benzthiazole-2-carboxylate:

[0742] Ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate wasprepared according to the procedure as outlined in Example 1, (Step 1).Starting from 6-fluoro-2-amino benzothiazole (10.0 g, 59.5 m.mol) andethyl bromopyruvate (17.4 g, 89.2 mmol), 3.0 g (19% Yield) of ethyl7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as abrown semi-solid. (M+H) 265.

[0743] Step 2: 7-fluoro- imidazo[2,1-b]-benzthiazole-2-methanol:

[0744] 7-Fluoro-imidazo[2,1-b]-benzthiazole-2-methanol was preparedstarting from Ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate(2.64 g, 0.01 mol) and LiBH₄ (50 mg) in THF at refluxing temperature for2 hrs. at the end, reaction mixture was quenched with ice cold water andacidified with 10 N. HCl. Reaction mixture was stirred for 1 hr andnuetralized with K₂CO₃. The separated residue was extracted withchloroform:methanol (3:1) and dried over anhydrous MgSO₄. It wasfiltered and concentrated. The crude reaction mixture was found to bepure and taken to next step with out any purification. Yeild: 1.5 g(68%) Semi solid; M+H 223.

[0745] Step 3: 2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole:

[0746] 2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole was preparedaccording to the procedure outlined in Example 1, (Step 3). Startingfrom 7-fluoro-imidazo[2,1-b]-benzthiazole-2-methanol (1.5 g 6.7 mmol) inmethylene chloride/DMF(300 mL: 50 mL) and active MnO₂ (12 g, excess),1.1 g (78% Yield) of the aldehyde derivative was isolated as brownsolid. (M+H) 221.

[0747] Step 4: 4-Nitrobenzyl-6-[(acetyloxy)(7-fluoro-midazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0748] 2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole (500 mg, 2.3 mmol)and the dry THF solution (40 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (875 mg, 2.3 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂:etherate (1.3g, 5 mmol) under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to a silicagel column, then the column was eluted with ethyl acetate:hexane (1:1).Collected fractions were concentrated under reduced pressure and themixture of diastereo isomers were taken to next step. Pale yellowamorphous solid; Yield: 330 mg, 22%; M+H 649.

[0749] Step 5:(5R),(6Z)-6-[(7-fluoro-imidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid:

[0750] 4-Nitrobenzyl-6-[(acetyloxy)(7-fluoro-imidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(710 mg, 1.07 mmol) was dissolved in THF (17 mL) and acetonitrile (36mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 1 N NaOH was added to adjust pH to 8.5. The filtrate was washedwith ethyl acetate and the aqueous layer was separated. The aqueouslayer was concentrated under high vacuum at 35° C. to give yellowprecipitate. The precipitate was filtered and washed with H₂O, MeCN,acetone to give the title compound. Yield: 80 mg, 19%; as yellowcrystals; mp 200 (dec); M+Na 396.

[0751]¹H NMR (DMSO-d₆) δ 6.53 (s, 1H), 6.63 (s, 1H), 7.1 (s, 1H), 7.45(t, 1H), 8.04 (m, 1H), 8,13-8.10 (m, 1H), 8.61 (s, 1H).

Example 15 Preparation of(5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid

[0752] Step 1: Preparation of ethyl5.8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazole-2-carboxylate

[0753] A mixture of-tetrahydro-4H-pyran-4-one (5.0 g, 50 mmol) in CCl₄(100 ml) at 0° C., SO₂Cl₂ (7.4 g, 55 mmol) was slowly added. After theaddition, reaction mixture was stirred at room temperature for 4 hrs andcarefully quenched with ice cold water. Recation mixture was washed welland dried over anhydrous MgSO₄. The organic layer was filtered andconcentrated. The colurless oil obtained was diisoolved in THF/EtOHcontaining thiourea (4.0 g, 52 mmol) and refluxed for 8 hrs. At the end,reaction mixture was cooled to room temperature and the separated,6,7-dihydro-4H-pyrano[4,3-d][1,3]thiazol-2-amine hydrochloride whitesolid was filtered. Yield. 4.5 g (47%); M.Pt. 115° C., (M+H) 157.

[0754] To a stirred mixture of,6,7-dihydro-4H-pyrano[4,3-d][1,3]thiazol-2-amine hydrochloride (4.0 g,20.8 mmol) was dissolved in anhydrous ethanol (100 ml) and sodiummethoxide (1.1 g, 21 mmol). This was stirred at room temperature for 30minutes and to this ethyl bromopyruvate (10.0 g) was added and stirredat room temperature for 2 hrs. Then it was refluxed for 48 hrs. At theend reaction mixture was cooled to room temperature and concentrated.The residue was extracted with chloroform and washed well with water.The product was purified by silica-gel column chromatography by elutingit with 50% ethyl acetae: hexane. Red semi-solid; Yield: 3.1 g, (59%)M+H 253.

[0755] The ester was reduced with LiBH₄ and the resultant alcohol wasoxidized with active MnO₂. The aldehyde obtained was taken to next step.

[0756] Step 3: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)(5,8-dihydro-6H-imidazo[2,1-b][1,3]pyrano[4,3-d][1,3]thiazol-2-yl)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0757] 2-Formyl-5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazole(208 mg, 1.0 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (400 mg, 1.1 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.2 g,3.0 mmol)under an argon atmosphere at room temperature. After cooling to−20° C., Et₃N (2.0 mL) was added in one portion. The reaction vessel wascovered with foil to exclude light. The reaction mixture was stirred for2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 400 mg, 62%; M.Pt. 78° C.; M+H636.

[0758] Step 4: Preparation of(5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid

[0759] 4-nitrobenzyl(5R)-6-[(acetyloxy)(5,8-dihydro-6H-imidazo[2,1-b][1,3]pyrano[4,3-d][1,3]thiazol-2-yl)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(500 mg, 0.79 mmol) was dissolved in THF (20 mL) and acetonitrile (10mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate waswashed with ethyl acetate and the aqueous layer was separated. Theaqueous layer was concentrated under high vacuum at 35° C. to give ayellow precipitate. The product was purified by HP21 resin reverse phasecolumn chromatography. Initially the column was eluted with deionizedwater (2 L) and latter with 10% acetonitrile:water. The fractionscontaining the product were collected and concentrated under reducedpressure at room temperature. The yellow solid was washed with acetone,filtered and dried. Yield: 85 mg, 30%; as yellow crystals; mp 205° C.;(M+H+Na) 383. ¹H NMR (DMSO-d₆) δ 2.8 (m, 2H), 4.0 (m, 2H), 4.6 (s, 2H),6.4 (s, 1H), 6.5 (s, 1H), 7.0 (s, 1H), 8.1 (s, 1H).

Example 16 Preparation of(5R),(6Z)-6-(imidazo[2,1-b]bebzothiazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0760] Step 1: Preparation ofimidazo[2,1-b][1,3]benzothiazol-7-ylmethanol: A solution of ethylimidazo[2,1-b][1,3]benzothizole-7-carboxylate (1.1 g, 4.5 mmol) in THF(50 ml) was slowly added to to a stirred solution of LiBH₄ (1 g) in THF(100 ml) at 0° C. The reaction mixture was refluxed for 2 hrs and cooledto room temperature. It was quenched with ice cold water andf carefullynuetralized with Con. HCl. The soltion was stirred at room temperaturefor 2 hrs and basified with K₂CO₃ (solid). At the end, reaction mixturewas extracted with chloform: methanol (3:1) and dried over anhydrousMgSO₄. It was filtered and concentrated. The product was pue enough andtaken to next step with out purification. Brown solid. M.t. 75° C.;(M+H) 205. Yield; 800 mg, (87%).

[0761] Step 2: Preparation of 7-formyl- imidazo[2,1-b][1,3]benzothiazol:

[0762] Imidazo[2,1-b][1,3]benzothiazol-7-ylmethanol (700 mg, 3.4 mmol)obtained by the above mentioned process was oxidiazed with active MnO₂(2 g) in CH₂Cl₂₌ under refluxing condition. The reaction mixture wasstirred for 6 hrs and cooled to room temperature. It was filtered andthrough celite and concentrated. The separated brown color solid wastriturated with diethyl ether and filtered. It was found to be pureenough and taken to next step with out purification. Yield. 400 mg(58%); (M+H) 203.

[0763] Step 3: 4-Nitrobenzyl-6-[(acetyloxy)(imidazo[2,1-b][,3]benzothiazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0764] 7-fomyl- imidazo[2,1-b][1,3]benzothiazol (260 mg, 1.3 mmol) andthe dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (500 mg, 1.14 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (390mg, 1.5 mmol)under an argon atmosphere at room temperature. Aftercooling to −20° C., Et₃N (2.0 mL) was added in one portion. The reactionvessel was covered with foil to exclude light. The reaction mixture wasstirred for 2 h at −20° C. and treated with acetic anhydride (1.04 mL)in one portion. The reaction mixture was warmed to 0° C. and stirred for15 h at 0° C. The mixture was diluted with ethyl acetate and washed with5% citric acid aqueous solution, saturated sodium hydrogen carbonate,and brine. The organic layer was dried (MgSO₄) and filtered through apad of Celite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 750 mg, 91%; M.pt. 82° C.; M+H630.

[0765] Step 5:5R),(6Z)-6-(imidazo[2,1-b]bebzothiazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid:

[0766] 4-Nitrobenzyl-6-[(acetyloxy)(imidazo[2,1-b][1,3]benzothiazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(900 mg, 1.4 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL)and 0.5 M phosphate buffer (pH 6.5, 20 mL) and hydrogenated over Pd/C(10%) at 40 psi pressure for 6 hrs. The reaction vessel was covered withfoil to exclude light. The reaction mixture was filtered, cooled to 3°C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate wasconcentarted and the aqueous layer was washed with ethyl acetate. Theaqueous layer was separated. The aqueous layer was concentrated underhigh vacuum at 35° C. to give a yellow precipitate. The product waspurified by HP21 resin reverse phase column chromatography. Initiallythe column was eluted with deionized water (2 L) and latter with 10%acetonitrile:water. The fractions containing the product were collectedand concentrated under reduced pressure at room temperature. The yellowsolid was washed with acetone, filtered and dried. Yield: 180 mg, 36%;as yellow crystals; mp 235° C.; (M+H+Na) 378.

[0767]¹H NMR (DMSO-d₆) δ 6.3 (s, 1H), 6.6 (s, 1H), 7.1 (s, 1H), 7.52 (s,1H), 8.1-8.5 (m, 3H), 8.7 (s, 1H).

Example 17 Preparation of(5R),(6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid

[0768] Step 1: Preparation ofbenzo[4,5]imidazo[2,1-b]thazole-2-carbaldehyde: To a stirred solution of2-mercapto benzimidazole (5.0 g, 33.3 mmol) and K₂CO₃ (4.59 g, 33.3mmol) in anhydrous DMF (100 mL) bromomalonaldehyde (4.99 g, 33.3) wasadded and heated fo 8 hrs at 80° C. At the end, reaction mixture wasconcentrated to dryness and ice cold water was added and nuetralzed with1 N HCl. The product was extarcted with chloroform and washed with waterand dried over anhydrous MgSO₄. It was filterd and concentrated. Theresidue was taken in DMF/acetic acid mixture (1:1) (100 ml) and heatedat 120° C. for 6 hrs. The reaction mixture was concentarted andextracted with chloroform; washed well with water and dried overanhydrous MgSO₄. It was filtered and concentarted. The separated solidwas triturated with diethyl ether and filtered. Yield: 4.2 g (62%);(M+H) 203.

[0769] Step 2: 4-Nitrobenzyl (5R)-6-[(acetyloxy)([1,3]thiazolo[3,2-a]benzimidazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0770] Benzo[4,5]imidazo[2,1-b]thazole-2-carbaldehyde (404 mg, 2 mmol)and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (772 mg, 2 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.65g, excess)under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 800 mg 63%; M.pt. 78° C.;(M+H) 630.

[0771] Step 3:(5R),(6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-2-ylmethylene0-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid:

[0772] 4-Nitrobenzyl (5R)-6-[(acetyloxy)([1,3]thiazolo[3,2-a]benzimidazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:(630 mg, 1.0 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL)and 0.5 M phosphate buffer (pH 6.5, 20 mL) and hydrogenated over Pd/C(10%) at 40 psi pressure for 6 hrs. The reaction vessel was covered withfoil to exclude light. The reaction mixture was filtered, cooled to 3°C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate wasconcentarted and the aqueous layer was washed with ethyl acetate. Theaqueous layer was separated. The aqueous layer was concentrated underhigh vacuum at 35° C. to give a yellow precipitate. The product waspurified by HP21 resin reverse phase column chromatography. Initiallythe column was eluted with deionized water (2 L) and latter with 10%acetonitrile:water. The fractions containing the product were collectedand concentrated under reduced pressure at room temperature. The yellowsolid was washed with acetone, filtered and dried. Yield: 190 mg, 50%;as yellow crystals; mp 240° C. (Dec); (M+H+Na) 378.

[0773]¹H NMR (DMSO-d₆) δ 6.3 (s, 1H), 6.4 (s, 1H), 6.6 (d, 2H),7.29-7.39 (m, 2H), 7.69-7.73 (t, 1H), 8.1-8.19 (m, 1H), 8.84 (s, 1H).

Example 18 Preparation of(5R),(6Z)-6-(7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-6-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid

[0774] Step 1: Preparation of7.9-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazole-2-carbaldehyde:

[0775] To a stirred solution of1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3(H)-thione [Prepared by theprocedure of T. takeshima, N. Oskada, E. Okabe and F. mineshima, J.Chem. Soc. Perkin. Trans. 1, 1277-1279, (1975)] (5.3 g, 37.85 mmol) andK₂CO₃ (10.4 g, 75 mmol) in anhydrous DMF (100 mL) bromomalonaldehyde(5.7 g, 37.85) was added and heated fo 8 hrs at 80° C. At the end,reaction mixture was concentrated to dryness and ice cold water wasadded and nuetralzed with 1N HCl. The product was extarcted withchloroform and washed with water and dried over anhydrous MgSO₄. It wasfilterd and concentrated. The residue was taken in DMF/acetic acidmixture (1:1) (100 ml) and heated at 120° C. for 6 hrs. The reactionmixture was concentarted and extracted with chloroform; washed well withwater and dried over anhydrous MgSO₄. It was filtered and concentarted.The product was purified by SiO₂ column chromatography by eluting itwith 75% ethyl acetate:hexane. Yield: 2.2 g (30%); M.Pt. 112° C.; (M+H)193.

[0776] Step 2: 4-Nitrobenzyl-(5R)-6-[(acetyloxy)(7,8-dihydro-8H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[0777]7,9-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazole-2-carbaldehyde(576 mg, 3 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.16 g, 3 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.65g, excess)under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 1.5 g, 83%; M.pt. 69° C.;(M+H) 620.

[0778] Step 3:(5R),(6Z)-6-(7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid

[0779] 4-Nitrobenzyl-(5R)-6-[(acetyloxy)(7,8-dihydro-8H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.2 g, 1.9 mmol) was dissolved in THF (30 mL) and acetonitrile (30 mL)and 0.5 M phosphate buffer (pH 6.5, 30 mL) and hydrogenated over Pd/C(10%) at 40 psi pressure for 6 hrs. The reaction vessel was covered withfoil to exclude light. The reaction mixture was filtered, cooled to 3°C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate wasconcentarted and the aqueous layer was washed with ethyl acetate. Theaqueous layer was separated. The aqueous layer was concentrated underhigh vacuum at 35° C. to give a yellow precipitate. The product waspurified by HP21 resin reverse phase column chromatography. Initiallythe column was eluted with deionized water (2 L) and latter with 10%acetonitrile:water. The fractions containing the product were collectedand concentrated under reduced pressure at room temperature. The yellowsolid was washed with acetone, filtered and dried. Yield: 420 mg, 38%;as yellow crystals; mp 190° C. (Dec); (M+H+Na) 368.

[0780]¹H NMR (DMSO-d₆) ¹H NMR (DMSO-d₆) δ 2.38-2.42 (m, 2H), 2.69-2.89(m, 4H), 6.57 (s, 1H), 6.58 (s, 1H), 7.36 (s, 1H), 8.53 (s, 1H).

Example 19 Preparation of(5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0781] Step 1: Preparation of ethyl5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-2-carboxylate.

[0782] A mixture of 2-chlorocyclohexanone (13.2 g, 100 mmol) andthiourea (8.0 g 101 mmol) was refluxed in ethanol: THF (1:2) for 16 hrs.The reaction mixture was cooled to room temperature and the separatedwhite solid was filtered. (12.0 g separated) This was dissolved inanhydrous ethanol (100 ml) and sodium methoxide (3.3 g, 63 mmol). Tothis ethyl bromopyruvate (15.0 g) was added and stirred at roomtemperature for 2 hrs. Then it was refluxed for 48 hrs. At the endreaction mixture was cooled to room temperature and concentrated. Theresidue was extracted with chloroform and washed well with water. Theproduct was purified by silica-gel column chromatography by eluting itwith 50% ethyl acetae: hexane. Red semi-solid; Yield: 6.2 g (39%); M+H251.

[0783] The ester was reduced with LiBH₄ and the resultant alcohol wasoxidized with active MnO₂. The aldehyde obtained was taken to next step.

[0784] Step 3: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)(5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0785] 5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-2-carbaldehyde(412 mg, 2.0 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (770 mg, 2 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.2 g,3.0 mmol)under an argon atmosphere at room temperature. After cooling to−20° C., Et₃N (2.0 mL) was added in one portion. The reaction vessel wascovered with foil to exclude light. The reaction mixture was stirred for2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 980 mg, 77%; M+H 634.

[0786] Step 4: Preparation of(5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0787] 4-nitrobenzyl(5R)-6-[(acetyloxy)(5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(980 mg, 1.55 mmol) was dissolved in THF (20 mL) and acetonitrile (10mL). Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 Mphosphate buffer (pH 6.5, 28 mL). The reaction vessel was covered withfoil to exclude light. The reaction mixture was vigorously stirred for 2h at room temperature. The reaction mixture was filtered, cooled to 3°C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate waswashed with ethyl acetate and the aqueous layer was separated. Theaqueous layer was concentrated under high vacuum at 35° C. to give ayellow precipitate. The product was purified by HP21 resin reverse phasecolumn chromatography. Initially the column was eluted with deionizedwater (2 L) and latter with 10% acetonitrile:water. The fractionscontaining the product were collected and concentrated under reducedpressure at room temperature. The yellow solid was washed with acetone,filtered and dried. Yield: 120 mg, 20%; as yellow crystals; mp 250° C.(Dec); (M+H+Na) 382. ¹H NMR (DMSO-d₆) δ 1.9 (m, 2H), 2.5 (m, 2H),3.2-3.4 (m, 4H), 6.6 (s, 1H), 7.1 (s, 1H), 7.5 (s, 1H), 8.1 (s, 1H).

Example 20 Preparation of(5R),(6Z)-8-[(9-methyl-9H-imidazo[1,2-a]benzimidazol-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0788] Step 1: Preparation of9-methyl-9H-imidazo[1,2-a]benzimidazole-2-carbaldehyde.

[0789] To stirred solution of LiBH₄ (1.79 g, 82 mmol) in THF at 0° C.,ethyl 9-methyl-9H-imidazo[1,2-a]benzimidazole-2-carboxylate (2.5 g, 10.3mmol) was added drop wise. The reaction mixture was refluxed for 2 hrsand cooled to room temperature. Ti was carefully quenched with icve coldwater and acidified with Con. HCl to pH 4. The reaction mixture wasstirred at room temperature for 1 hr and basified with K₂CO₃. Theresidue was extracted with chloroform;methanol (3:1) and dried overanhydrous MgSO₄. It was filtered and concentrated. Yield. 1.3 g (65%).(M+H) 202. The resdue (1.3 g, 6.4 mmol) was oxidised with MnO₂ (5.0 g)in CH₂Cl₂ under refluxing condition. After the completion, reactionmixture was filtered and concentrated. It was purified by SiO₂ columnchromatography by eluting it with 1:1 ethyl acetate:hexane. Brown solid.Yield. 330 mg (25%); (M+H) 200.

[0790] Step 2: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)(9-methyl-9H-imidazo[1,2-a]benzimidazole-2-)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

[0791] 9-methyl-9H-imidazo[1,2-a]benzimidazole-2-carbaldehyde. (330 mg,1.65 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (770 mg, 2 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.2 g,3.0 mmol)under an argon atmosphere at room temperature. After cooling to−20° C., Et₃N (2.0 mL) was added in one portion. The reaction vessel wascovered with foil to exclude light. The reaction mixture was stirred for2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 330 mg, 31%; (M+H) 628.

[0792] Step 3: Preparation of(5R),(6Z)-8-[(9-methyl-9H-imidazo[1,2-a]benzimidazol-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0793] 4-nitrobenzyl(5R)-6-[(acetyloxy)(9-methyl-9H-imidazo[1,2-a]benzimidazole-2-)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:(1 g, 1.6 mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL).Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 M phosphatebuffer (pH 6.5, 28 mL). The reaction vessel was covered with foil toexclude light. The reaction mixture was vigorously stirred for 2 h atroom temperature. The reaction mixture was filtered, cooled to 3° C.,and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate waswashed with ethyl acetate and the aqueous layer was separated. Theaqueous layer was concentrated under high vacuum at 35° C. to give ayellow precipitate. The product was purified by HP21 resin reverse phasecolumn chromatography. Initially the column was eluted with deionizedwater (2 L) and latter with 10% acetonitrile:water. The fractionscontaining the product were collected and concentrated under reducedpressure at room temperature. The yellow solid was washed with acetone,filtered and dried. Yield: 140 mg, 23%; as yellow crystals; mp 220° C.(Dec); (M+H+Na) 375. ¹H NMR (DMSO-d₆) δ 3.4 (s, 3H), 6.54 (s, 1H), 6.56(s, 1H), 7.01 (s, 1H), 7.21 (t, 1H), 7.3 (t, 1H), 7.56 (d, 1H), 7.85 (d,1H), 8.1 (s, 1H).

Example 21 Preparation of(5R,6Z)-7-oxo-6-(4H-thieno[2′,3′:4,5]thiopyrano[2,3-b]pyridin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid (Sodium Salt)

[0794] Step 1: 2.3 dihydro-4H-thiopyrano[2,3-b]pyridin-4-one:

[0795] A solution of 14 g. (61.6 mmol)3-(3-Carboxy-2-pyridylthio)propionic Acid [prepared as described inlit.: J. Heterocyclic Chem., 37.379(2000)]and 15 g.(185 mmol, 3 eqs) ofanhydrous sodium acetate, in 200 mL. of acetic anhydride was refluxed(160° C.) under stirring, N₂ atm, dry conditions, for 2 hours. Cooled,diluted with 300 mL of water, basified with 30% ammonium hydroxidesolution to pH 8-9, extracted with 3×200 mL chloroform. Combinedorganics washed with 2×60 mL Sodium bicarbonate (satn.sol), water,dried, evaporated, gave 2.8 g. (27%) of the title compound, reddishsolid, m.p.66-8° C., (M+H)⁺=166.2.

[0796] Step 2: 4-chloro-2H-thiopyrano[2,3b]pyridine-3-carbaldehyde:

[0797] A solution of 6.6 g.(43 mmol, 1 eq) of phosphorous oxychloride in30 mL methylene chloride was dropwise added to 3.95 g (43 mmol, 1.25eqs) of anhydrous dimetylformamide (0° C., stirring, N₂ atm, dryconditions) with such a rate to maintain temperature between 0-5° C.; RMwas stirred at RT for 2 hours, cooled to 0° C., and a solution of 8.9g.(54 mmol, 1.25 eqs.) of 2,3 dihydro-4H-thiopyrano[2,3-b]pyridin-4-onein 30 mL of methylene chloride was dropwise added over a 20 min. period.RM stirred at RT for 2 hours, poured over crushed ice:sodium acetate 4:1mixture, extracted with 4× 150 mL methylene chloride, combined organicswashed with water, dried, evaporated, gave 7.76 g (68%) of the titlecompound, brownish solid, m.p.56-8° C., (M+H)⁺=212.6.

[0798] Step 3: Ethyl 4H-thieno[2′3′:4,5]thiopyrano[2,3b]pyridine-2carboxylate:

[0799] To a solution of 7.5 g. (35 mmol, 1 eq.) of4-chloro-2H-thiopyrano[2,3b]pyridine-3-carbaldehyde in 25o mL ofmethylene chloride were added (under stirring, N₂ atm, dry conditions):4.7 g.(39 mmol, 1.1 eqs) of ethyl mercaptoacetate, and 7.2 g. (71 mmol,2 eqs) of triethylamine in 30 mL of methylene chloride. RM was refluxedfor 2 hours, quenched with 100 mL of water, organics separated, watersextracted with 4×150 mL of methylene chloride, combined organics dried,evaporated. Residue purified on a silicagel column, using hexane:ethylacetate 3:1 as a solvent, gave 7.6 g. (78%) of the title compound,yellow crystals, m.p. 113-5° C., (M+H)⁺=278.3.

[0800] Step 4: 4H-thieno[2′,3′:4,5]thiopyrano[2,3b]pyridin-2-ylmethanol:

[0801] To a cold solution of 7.5 g.(27 mmol) of Ethyl4H-thieno[2′3′:4,5]thiopyrano[2,3b]pyridine-2 carboxylate in 300 mL ofdry tetrahydrofuran (0° C., N₂ atm, dry condition) was dropwise added 60mL (60 mmol, 2.1 eqs) of 1 M cold solution of Lithium Aluminum Hydridein tetrahydrofuran, and RM stirred at RT untill the SM disappeared(monitored by TLC/MS). Cooled to 0° C., RM was quenced with aquous 2Nformic acid solution to neutral pH=8, and stirred at RT for 2 hours,filtered, filtrate extracted 4×200 mL methylene chloride, combinedorganics dried, evaporated gave 6.0 g. (94%) of the desired compound,yellow crystals, m.p.112-4° C., (M+H)⁺=236.4.

[0802] Step 5:4H-thieno[2′,3′:4,5]thiopyrano[2.3b]pyridin-2-carbaldehyde:

[0803] To a solution of 3.0 g.(12.8 mmol) of4H-thieno[2′,3′:4,5]thiopyrano[2,3b]pyridin-2-ylmethanol in 200 mL ofchloroform, was added 9.0 g.(80 mmol, 7 eqs) of activatedmanganese(IV)oxide, and RM refluxed under stirring, N₂ atm., for 12hours. Filtered trough a celite pad, filtrate evaporated, and residuepurified on a silicagel column, gave 2.5 g.(86%) of the title compound,yellow crystals, m.p. 93-5° C., (M+H)⁺=234.4.

[0804] Step 6:4-nitrobenzyl(5R)-6-[(acetyloxy)(4H-thieno[2′,3′:4,5]thiopyrano[2,3b]pyridin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-ene-2carboxylate

[0805] In a sealed dry r.b. flask, flushed with N₂, were added:4H-thieno[2′,3′:4,5]thiopyrano[2,3b]- pyridin-2-carbaldehyde 0.6 g.(2.57 mmol, 1 eq), anhydrous THF (15 mL), anhydrous ACN (15 mL), 0.520g.(2.8 mmol, 1.1 eqs) anhydrous MgBr2, and RM stirred at RT for 30 min.To the RM was added 2.5 mL (14 mmol, 5.4 eqs) of anhydroustriethylamine, 10 mL of anhydrous THF, RM cooled at (−20° C.), and 0.95g.(2.5 mmol, 1 eq) of bromopenam was added. RM stirred at (−20° C.) for6 hours. At the same temperature, 3 mL (3 mmol, 1.15 eqs) of aceticanhydride was added, RM stirred for 15 min and kept at 0° C. for 12hours, evaporated to dryness, residue extracted with 5×80 mL ethylacetate. Organic solvent evaporated, and residue purified an a silicagelcolumn (solvent hexane:ethyl acetate 4:1), gave 0.880 g.(52%) of thetitle compound, yellowish crystals, m.p. 141-3° C., (M+H)⁺=661.6.

[0806] Step 7:(5R,6Z)-7-oxo-6-(4H-thieno[2′,3′:4.5]thiopyrano[2.3-b]pyridin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid (Sodium Salt)

[0807] A solution of4-nitrobenzyl(5R)-6-[(acetyloxy)(4H-thieno[2′,3′:4,5]thiopyrano[2,3b]pyridin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0.]hept-ene-2carboxylate0.8 g.(1.21 mmol, 1 eq) in 40 mL THF and 40 mL phosphate buffer solution(pH=6.36) was hydrogenated at 40 psi for 3 hours in the presence of 0.4g. Palladium on Carbon 10% catalyst. RM filtrated trough celite pad,filtrate adjusted to pH=8.0, concentrated in vacuo, residue purified ona reverse-phase column (amberlite), using 5%.10% ACN/water mixture assolvent, gave 0.103 g.(21%) of the title compound, reddish crystals,m.p.362.4° C., (M+H)⁺=409.5. 1H NMR: (DMSO-d₆) δ 4.12 (s, 2H), 6.49 (s,1H), 6.53 (s, 1H); 7.22 (d, 1H); 7.34 (s, 1H); 7.41 9 s, 1H), 7.76 (t,1H); 8.28 (d, 1H).

Example 22 Preparation of(5R,6Z)-6-[(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0808] Step 1: Preparation of(8-Methyl-6,7-dihydro-5H-cyclopenta[d][1,2,4triazolo[1,5-a]pyrimidin-2-yl)-methanol

[0809] To a round bottomed flask was loaded 3.78 grams of2-acetylcyclopentanone, 3.52 grams of(5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 50 ml 2-methoxyethanol.The mixture was refluxed for 18 hours. Then it was cooled down to 23° C.and concentrated to 5 ml. Then 50 ml ethyl ether was added and theprecipitate was filtered and vacuum dried to yielded 2.0 grams ofproduct. This compound was used directly for the next step. MS: 205.2(M+H). ¹H-NMR(DMSO): δ 5.55 (t, 1H, OH, J=6.2 Hz), 4.63 (d, 2H, J=6.2Hz), 3.28 (m, 2H), 3.02 (t, 2H, CH2, J=6.8 Hz), 2.51 (s, 3H, CH3), 2.27(m, 2H, CH2).

[0810] Step 2: Preparation of8-Methyl-6,7-dihydro-5H-cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde

[0811] To a round bottomed flask was loaded 0.17 ml of DMSO and 1 mldichloromethane. The mixture was cooled to −50˜−60° C. Then a mixture of0.1 ml oxallyl chloride and 2 ml dichloromethane was injected in intothe flask all at once. The mixture was stirred at the same temperaturefor another 5 minutes. Then 0.174 grams of(8-Methyl-6,7-dihydro-5H-cyclopenta[d][1,2,4] triazolo[1,5-a]pyrimidin-2-yl)-methanol in 2 ml dichloromethane was added within2 minutes. The mixture was stirred at −50˜−60° C. for fifteen minutesand 0.7 ml triethylamine was next added. After another five minutes thereaction media was warmed up to 23° C. and a mixture of 20 ml water and200 ml dichloromethane was added. The organic layer was dried overmagnesium sulfate. Filter off the drying agent and concentrate thefiltrate yielded 0.153 grams of product (89%). MS: 203.1 (M+H).H-NMR(CDCl3): δ 10.24 (s, 1H), 3.49 (m, 2H), 3.15 (m, 2H), 2.67 (s, 3H,CH3), 2.44 (m, 2H, CH2).

[0812] Step 3: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[0813]8-Methyl-6,7-dihydro-5H-cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde(153 mg, 0.75 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (385 mg, 1 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.2 g,3.0 mmol)under an argon atmosphere at room temperature. After cooling to−20° C., Et₃N (2.0 mL) was added in one portion. The reaction vessel wascovered with foil to exclude light. The reaction mixture was stirred for2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 200 mg, 42%; (M+H) 631.

[0814] Step 4: Preparation of(5R,6Z)-6-[(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0815] 4-nitrobenzyl(5R)-6-[(acetyloxy)(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(200 mg, 0.31 mmol) was dissolved in THF (20 mL) and acetonitrile (20mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C(10%) (200 mg) under 40 psi pressure. At the end, reaction mixture wasfiltered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to8.5. The filtrate was washed with ethyl acetate and the aqueous layerwas separated. The aqueous layer was concentrated under high vacuum at35° C. to give a yellow precipitate. The product was purified by HP21resin reverse phase column chromatography. Initially the column waseluted with deionized water (2 L) and latter with 10%acetonitrile:water. The fractions containing the product were collectedand concentrated under reduced pressure at room temperature. The yellowsolid was washed with acetone, filtered and dried. Yield: 15 mg, 13%; asyellow crystals; mp 250° C. (Dec); (M+H+Na) 378. ¹H NMR (DMSO-d₆) δ 6.80(s, 1H), 6.76 (s, 1H), 6.25 (s, 1H), 3.24 (m, 2H), 2.96 (m, 2H), 2.49(s, 3H), 2.25 (m, 2H).

Example 23 Preparation of(5R,6Z)-6-{[7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0816] Step 1: Preparation of2-Hydroxymethyl-8,9-dihydro-6H-1,3,4,7,9b-pentaaza-cyclopenta[a]naphthalene-7-carboxylicAcid Ethyl Ester

[0817] To a round bottomed flask was loaded 8.56 grams of4-oxo-piperidine-1-carboxylic acid ethyl ester, 10.3 ml ofdimethylformamide dimethylacetal, and the mixture was refluxed at 90° C.for two hours. Then it was poured into 75 ml water and extracted with2×250 ml dichloromethane. The combined organic layers was washed with 50ml brine and dried over magnesium sulfate. Filter off the drying agentand concentrate gave 28 grams of3-Dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid ethyl ester.This material (12.8 grams) was then loaded into a round bottomed flaskalong with 3.42 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and100 ml 2-methoxyethanol. The mixture was refluxed for 18 hours. Then itwas cooled down to 23° C. and concentrated to 5 ml. Then 50 ml ethylether was added and the precipitate was filtered and vaccum dried toyielded 1.5 grams of product. MS: 278.1 (M+H). H-NMR(CDCL3): δ 8.60 (s,1H), 4.98 (s, 2H), 4.78 (s, 2H, CH2), 4.22 (q, 2H, J=4.8 Hz), 3.75 (t,2H, CH2, J=4 Hz), 3.51 (t, 2H, J=4 Hz), 1.32 (m, 3H, CH3, J=4.8 Hz).

[0818] Step 2: Preparation of2-Formyl-8,9-dihydro-6H-1,3,4,7,9b-pentaaza-yclopenta[a]naphthalene-7-carboxylicAcid Ethyl Ester

[0819]2-Hydroxymethyl-8,9-dihydro-6H-1,3,4,7,9b-pentaaza-cyclopenta[a]naphthalene-7-carboxylicacid ethyl ester (831 mg, 3 mmol) was converted to2-formyl-8,9-dihydro-6H-1,3,4,7,9b-pentaaza-yclopenta[a]naphthalene-7-carboxylicacid ethyl ester (690 mg, 89% Yield) by the procedure outlined inexample 22, (step 2).

[0820] MS: 276.1 (M+H). H-NMR(CDCl3): δ 10.24 (s, 1H), 8.76 (s, 1H),4.86 (s, 2H), 4.23 (q, 2H, CH2, J=7.2 Hz), 4.13 (t, 2H, CH2, J=7.2 Hz)3.39 (t, 2H, CH2, J=5.7 Hz), 1.34 (t, 3H, CH3, J=7.2 Hz).

[0821] Step 3: ethyl2-[(acetyloxy)((5R)-6-bromo-2-{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-6-yl)methyl]-8.9-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine-7(6H)-carboxylate

[0822]2-formyl-8,9-dihydro-6H-1,3,4,7,9b-pentaaza-yclopenta[a]naphthalene-7-carboxylicacid ethyl ester (550 mg, 2 mmol) and the dry THF solution (20 mL) of(5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (770 mg, 2 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.2 g,3.0 mmol)under an argon atmosphere at room temperature. After cooling to−20° C., Et₃N (2.0 mL) was added in one portion. The reaction vessel wascovered with foil to exclude light. The reaction mixture was stirred for2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 220 mg, 15%; (M+H) 703.

[0823] Step 4: Preparation of(5R,6Z)-6-{[7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0824] ethyl2-[(acetyloxy)((5R)-6-bromo-2-{[(4-nitrobenzyl)oxy]carbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-6-yl)methyl]-8,9-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine-7(6H)-carboxylate(220 mg, 0.28 mmol) was dissolved in THF (20 mL) and acetonitrile (20mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C(10%) (200 mg) under 40 psi pressure. At the end, reaction mixture wasfiltered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to8.5. The filtrate was washed with ethyl acetate and the aqueous layerwas separated. The aqueous layer was concentrated under high vacuum at35° C. to give a yellow precipitate. The product was purified by HP21resin reverse phase column chromatography. Initially the column waseluted with deionized water (2 L) and latter with 10%acetonitrile:water. The fractions containing the product were collectedand concentrated under reduced pressure at room temperature. The yellowsolid was washed with acetone, filtered and dried. Yield: 15 mg, 2%;Yellow crystals; mp>250° C. (Dec); (M+H+Na) 449. ¹H NMR (DMSO-d₆) δ 8.61(s, 1H), 7.01 (s, 1H), 6.90 (s, 1H), 6.44 (s, 1H), 4.74 (m, 2H, CH2),4.13 (q, 2H, J=5.4 Hz), 3.84 (s, m, 2H, CH2), 1.22 (t, 3H, CH3, J=5.7Hz).

Example 24 Preparation of(5R,6Z)-6-(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7°-[1,2,4triazolo[1,5-a]quinazolin]-2′-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0825] Step 1: Preparation of2-Hydroxymethyl-8,9-dihydro-6H-[1,2,4]triazolo[1,5-a]quinazolin-7-ethyleneKetal

[0826] To a round bottomed flask was loaded 15.6 g of 1,4-cyclohexadionemono-ethylene ketal, 11.9 g of dimethylformamide dimethylacetal, and themixture was refluxed at 90° C. for two hours. Then it was poured into 75ml water and extracted with 2×250 ml dichloromethane. The combinedorganic layers was washed with 50 ml brine and dried over magnesiumsulfate. Filter off the drying agent and concentrate gave 28 grams of3-Dimethylaminomethylene-4-oxo-cyclohexane. The crude product was thenloaded into a round bottomed flask along with 11.9 grams of(5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 100 ml 2-methoxyethanol.The mixture was refluxed for 18 hours. Then it was cooled down to 23° C.and concentrated to 5 ml. Then 50 ml ethyl ether was added and theprecipitate was filtered and vaccum dried to yielded 2.0 grams (8%Yield) of product. MS: 263 (M+H). H-NMR(CDCL3): δ 8.51 (s, 1H), 5.17 (s,2H, CH2), 4.08 (s, 4H, OCH2CH₂O), 3.42 (t, 2H, CH2, J=5.1 Hz), 3.07 (s,2H, CH2), 2.15 (t, 3H, CH3, J=5.1 Hz).

[0827] Step 2: Preparation of7-ethyleneketal-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazoline-2-carbaldehyde

[0828] To a round bottomed flask was loaded 5 ml of DMSO and 5 mldichloromethane. The mixture was cooled to −50˜−60° C. Then a mixture of1 ml oxallyl chloride and 5 ml dichloromethane was injected in into theflask all at once. The mixture was stirred at the same temperature foranother 5 minutes.2-Hydroxymethyl-8,9-dihydro-6H-[1,2,4]triazolo[1,5-a]quinazolin-7-ethyleneketal (1.31 g, 5 mmol) in 20 ml dichloromethane was added within 2minutes. The mixture was stirred at −50˜−60° C. for fifteen minutes and0.7 ml triethylamine was next added. After another five minutes thereaction media was warmed up to 23° C. and a mixture of 20 ml water and200 ml dichloromethane was added. The organic layer was dried overmagnesium sulfate. Filter off the drying agent and concentrate thefiltrate yielded 910 mg of product (70%). MS: 261 (M+H). H-NMR(CDCl3): δ10.26 (s, 1H), 8.66 (s, 1H), 4.08 (s, 4H, OCH2CH₂O), 3.49 (t, 2H, J=6.9Hz), 3.11 (s, 2H), 2.18 (t, 3H, CH3, J=6.9 Hz), 2.44 (m, 2H, CH2).

[0829] Step 3: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolor[1,5-a]quinazolin]-2′-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[0830]7-Ethyleneketal-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazoline-2-carbaldehyde(780 mg, 3 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.15 g g, 3 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.2 g,3.0 mmol)under an argon atmosphere at room temperature. After cooling to−20° C., Et₃N (2.0 mL) was added in one portion. The reaction vessel wascovered with foil to exclude light. The reaction mixture was stirred for2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 300 mg, 15%; (M+H) 688.8.

[0831] Step 4: Preparation of Preparation of(5R,6Z)-6-(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolo[1,5-a]quinazolin]-2′-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0832] 4-nitrobenzyl(5R)-6-[(acetyloxy)(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolo[1,5-a]quinazolin]-2′-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(300 mg, 0.43 mmol) was dissolved in THF (20 mL) and acetonitrile (20mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C(10%) (200 mg) under 40 psi pressure. At the end, reaction mixture wasfiltered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to8.5. The filtrate was washed with ethyl acetate and the aqueous layerwas separated. The aqueous layer was concentrated under high vacuum at35° C. to give a yellow precipitate. The product was purified by HP21resin reverse phase column chromatography. Initially the column waseluted with deionized water (2 L) and latter with 10%acetonitrile:water. The fractions containing the product were collectedand concentrated under reduced pressure at room temperature. The yellowsolid was washed with acetone, filtered and dried. Yield: 15 mg, 9%;Yellow crystals; mp>250° C. (Dec); (M+H+Na) 435.9. ¹H NMR (DMSO-d₆) δ8.50 (s, 1H), 6.97 (s, 1H), 6.85 (s, 1H), 6.38 (s, 1H), 4.05 (s, 4H,OCH2CH₂O), 3.28 (m, 2H), 3.07 (s, 2H), 2.13 (t, 3H, CH3, J=4.8 Hz).

Example 25 Preparation of(5R,6Z)-6-[(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0833] Step 1: Preparation of(5-Methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazolin-2-yl)-methanol:

[0834] To a round bottomed flask was loaded 4.2 grams of2-acetylcyclohexanone, 3.52 grams of(5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 50 ml 2-methoxyethanol.The mixture was refluxed for 18 hours. Then it was cooled down to 23° C.and concentrated to 5 ml. Then 50 ml ethyl ether was added and theprecipitate was filtered and vacuum dried to yielded 3.32 grams ofproduct Yield. 49%. This compound was used directly for the next step.MS: 219.2 (M+H). H-NMR(DMSO): δ 5.49 (t, 1H, OH, J=6 Hz), 4.61 (d, 2H,J=6 Hz), 3.24 (m, 2H), 2.93 (m, 2H), 2.69 (s, 3H), 2.52 (s, 2H), 1.84(m, 4H).

[0835] Step 2: Preparation of5-Methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazoline-2-carbaldehyde

[0836] To a round bottomed flask was loaded 1 ml of DMSO and 5 mldichloromethane. The mixture was cooled to −50˜−60° C. Then a mixture of1 ml oxallyl chloride and 2 ml dichloromethane was injected in into theflask all at once. The mixture was stirred at the same temperature foranother 5 minutes. Then 0.218 grams of(5-Methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazolin-2-yl)-methanolin 2 ml dichloromethane was added within 2 minutes. The mixture wasstirred at −50˜−60° C. for fifteen minutes and 0.7 ml triethylamine wasnext added. After another five minutes the reaction media was warmed upto 23° C. and a mixture of 20 ml water and 200 ml dichloromethane wasadded. The organic layer was dried over magnesium sulfate. Filter offthe drying agent and concentrate the filtrate yielded 0.216 grams ofproduct (99%). MS: 217.1 (M+H). H-NMR(CDCl3): 610.20 (s, 1H), 3.23 (m,2H), 2.78 (m, 2H) 2.63 (s, 3H, CH3), 2.00 (m, 4H),

[0837] Step 3: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolor[1,5-a]quinazolin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[0838]5-Methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazoline-2-carbaldehyde(432 mg, 2 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (770 mg, 2 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (1.2 g,3.0 mmol)under an argon atmosphere at room temperature. After cooling to−20° C., Et₃N (2.0 mL) was added in one portion. The reaction vessel wascovered with foil to exclude light. The reaction mixture was stirred for2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereomers were taken to the nextstep. Pale yellow amorphous solid; Yield: 600 mg, 47%; (M+H) 644.7.

[0839] Step 4: Preparation of Preparation of(5R,6Z)-6-[(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-Yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0840] 4-nitrobenzyl(5R)-6-[(acetyloxy)(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(600 mg, 0.93 mmol) was dissolved in THF (20 mL) and acetonitrile (20mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C(10%) (200 mg) under 40 psi pressure. At the end, reaction mixture wasfiltered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to8.5. The filtrate was washed with ethyl acetate and the aqueous layerwas separated. The aqueous layer was concentrated under high vacuum at35° C. to give a yellow precipitate. The product was purified by HP21resin reverse phase column chromatography. Initially the column waseluted with deionized water (2 L) and latter with 10%acetonitrile:water. The fractions containing the product were collectedand concentrated under reduced pressure at room temperature. The yellowsolid was washed with acetone, filtered and dried. Yield: 37 mg, 11%; asyellow crystals; mp 250° C. (Dec); (M+H+Na) 392. ¹H NMR (DMSO-d₆) δ 6.90(s, 1H), 6.85 (s, 1H), 6.28 (s, 1H), 2.98 (m, 2H), 2.77 (m, 2H), 2.55(m, 3H), 1.78 (m, 4H).

Example 26 Preparation of(5R,6Z)-6-[(5-methoxy-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0841] Step 1: Preparation of4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine

[0842] (S M:Ross, L. O.; Goodman, L.; Baker, B. R. J. Am. Chem. Soc.1959, 81, 3108) 5.3 grams of4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in200 ml xylene and 30 ml absolute methanol. Then 5.4 gram for sodiummethoxide was added and the mixture was refluxed for 3 hours. Then thesolvent was removed in vacuo and 100 ml water was added to the residue.Filter and wash the cake with water (50 ml). The solid was furthervacuumed to dry for several hours. The desired product weighed 4.8 gram(98% yield). Mp: 133.8˜134.9° C.; MS: 166.2.0 (M+H)

[0843] Step 2: Preparation of5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carboxylic AcidEthyl Ester

[0844] 4.8 gram (29 mmol)4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in100 ml dry THF. Bromopyruvate (5.4 ml,) was then added dropwise with infive minutes. The mixture was stirred at 23° C. for one hour. It wasthen filtered and washed with ether to give 8.7 gram of solid. Thissolid was then dissolved in 50 ml ethanol and refluxed for two hours.The reaction mixture was cooled to room temperature and partitionedbetween 350 ml chloroform and 200 ml saturated sodium bicarbonate. Theorganic layer was separated and dried over magnesium sulfate. Filter offthe drying agent and concentrate to give 5.3 gram of product (70%Yield). MP: 105-106° C. (M+H) 262.

[0845] Step 3: Preparation of5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carbaldehyde

[0846] 5.2 grams (19.8 mmol)5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carboxylic acidethyl ester was dissolved in 40 ml dichloromethane and then cooled to−78° C. DIBAL (1 M, 30 ml, 1.5 eq.) was then added within five minutes.The reaction media was then quenched with 2 ml ethanol and partitionedbetween 350 ml dichloromethane and 100 ml 1 N sodium hydroxide. Theaqueous layer was washed with another 150 ml chloroform and the combinedorganic layer was dried over magnesium sulfate and filtered andconcentrated to give the corresponding alcohol. The alcohol is thendissolved in 150 ml dichloromethane and 10 grams of manganese dioxide isthen added. The mixture was stirred at 23° C. for two hours. Thereaction mixture was then filtered through a pad of celite andconcentrated to give 1.1 gram (68%) of the desired aldehyde. MP:235.2˜236.3° C.; MS: 218.1 (M+H)

[0847] Step 4: Preparation of6-[acetoxy-(5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl Ester

[0848] A 30 ml acetonitrile solution of5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carbaldehyde (660mg, 3 mmol) was added 1.03 gram of magnesium bromide etherate. Themixture was stirred at 23° C. for half an hour. Then a 30 ml dry THFsolution of the6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid4-nitro-benzyl ester (1.155 gram, 1 eq.) was injected within a minuteand the reaction mixture was then cooled to −20° C. Triethylamine (0.7ml, eq.) was then injected and the reaction mixture was stirred for fivehours at −20° C. Then acetic anhydride (0.377 ml, eq.) was injected andthe reaction mixture was left at zero degree for 18 hours. The reactionmedia was then diluted with 400 ml ethyl acetate and washed with 100 ml5% citric acid, 100 ml saturated sodium bicarbonate, and 100 ml brine.The organic layer was then dried over magnesium sulfate, filtered andconcentrated. Flash column chromatography using 20% ethyl acetate inhexane gave 1.8 gram product. (93% Yield); MP: 118.7-119.1° C.; MS:645.9 (M+H)

[0849] Step 5: Preparation of6-(5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0850]6-[acetoxy-(5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (966 mg, 1.4 mmol) was suspended in 20 ml THFand 20 ml pH=6.5 aqueous phosphate buffer. The mixture was thensubjected to 45 psi hydrogen for two hours. Then it was filtered througha pad of celite and concentrated in vacuo to remove most of the THF. Thesolution was then cooled to zero degree and basified to pH=8 with 1 Nsodium hydroxide. Then it was purified via reverse phase HPLC using 1liter of water followed by 5%-25% acetonitrile and water. Water was thenremoved through concentrate in vacuo and 100 mg of product wascollected. MP: >250° C.

[0851]¹H-NMR: (300 MHz, D₂O) δ 10.12 (s, 1H), 9.29 (s, 1H), 8.81 (s,1H), 8.78 (s, 1H), 6.19 (s, 3H), 5.36 (m, 2H), 5.05 (m, 2H), 4.43 (m,2H).; MS: 371.2 (M+H).

Example 27 Preparation of(5R,6Z)-6-({5-[2-(benzyloxy)ethoxy]-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl}methylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0852] Step 1: Preparation of4-benzyloxyethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine

[0853] (S M:Ross, L. O.; Goodman, L.; Baker, B. R. J. Am. Chem. Soc.1959, 81, 3108) To stirred suspension of NaH (60% 552 mg) in THF2-benzyloxyethanol (3.38 g, 20 mmol) was slowly added at roomtemperature. After the addition,, 3.28 grams (19.4 mmol) of4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in200 ml THF and added to it and the mixture was refluxed for 3 hours.Then the solvent was removed in vacuo and 100 ml water was added to theresidue. The product was extracted with chloroform; washed well withwater and dried over anhydrous MgSO₄. It was filtered and concentrated.Low melting solid; Yield: 4.2 gram (73%); (M+H) 286.1

[0854] Step 2: Preparation of5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carboxylicAcid Ethyl Ester

[0855] 6.0 gram (21 mmol) of4-benzyloxyethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine wasdissolved in 100 ml dry THF. Bromopyruvate (8 ml,) was then addeddropwise with in five minutes. The mixture was stirred at 23° C. for onehour. It was then filtered and washed with ether to give a solid. Thissolid was then dissolved in 50 ml ethanol and refluxed for two hours.The reaction mixture was cooled to room temperature and partitionedbetween 350 ml chloroform and 200 ml saturated sodium bicarbonate. Theorganic layer was separated and dried over magnesium sulfate. Filter offthe drying agent and concentrate to give 5.36 gram of product (67%Yield). (M+H) 382.1

[0856] Step 3: Preparation of5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carbaldehyde

[0857] 3.81 grams (10 mmol)5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carboxylicacid ethyl ester was dissolved in 40 ml dichloromethane and then cooledto −78° C. DIBAL (1 M, 30 ml, 1.5 eq.) was then added within fiveminutes. The reaction media was then quenched with 2 ml ethanol andpartitioned between 350 ml dichloromethane and 100 ml 1 N sodiumhydroxide. The aqueous layer was washed with another 150 ml chloroformand the combined organic layer was dried over magnesium sulfate andfiltered and concentrated to give the corresponding alcohol. The alcoholis then dissolved in 150 ml dichloromethane and 10 grams of manganesedioxide is then added. The mixture was stirred at 23° C. for two hours.The reaction mixture was then filtered through a pad of celite andconcentrated to give 2.25 gram (67%) of the desired aldehyde. MS: 338(M+H)

[0858] Step 4: Preparation of6-[acetoxy-(5-[2-(benzyloxy)emethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid 4-nitro-benzyl Ester

[0859] A 30 ml acetonitrile solution of5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carbaldehyde(676 mg, 2 mmol) was added 1.03 gram of magnesium bromide etherate. Themixture was stirred at 23° C. for half an hour. Then a 30 ml dry THFsolution of the6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid4-nitro-benzyl ester (770 mg, 2 mmol) was injected within a minute andthe reaction mixture was then cooled to −20° C. Triethylamine (0.7 ml,eq.) was then injected and the reaction mixture was stirred for fivehours at −20° C. Then acetic anhydride (0.377 ml, eq.) was injected andthe reaction mixture was left at zero degree for 18 hours. The reactionmedia was then diluted with 400 ml ethyl acetate and washed with 100 ml5% citric acid, 100 ml saturated sodium bicarbonate, and 100 ml brine.The organic layer was then dried over magnesium sulfate, filtered andconcentrated. Flash column chromatography using 20% ethyl acetate inhexane gave 1.05 gram product. (68% Yield); MS: 765.8 (M+H)

[0860] Step 5: Preparation of Preparation of(5R,6Z)-6-((5-[2-(benzyloxy)ethoxy]-7,8-dihydro-6H-cyclopentarelimidazor[1,2-a]pyrimidin-2-yl]methylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0861]6-[acetoxy-(5-[2-(benzyloxy)emethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (966 mg, 1.2 mmol) was suspended in 20 ml THFand 20 ml pH=6.5 aqueous phosphate buffer. The mixture was thensubjected to 45 psi hydrogen for two hours. Then it was filtered througha pad of celite and concentrated in vacuo to remove most of the THF. Thesolution was then cooled to zero degree and basified to pH=8 with 1 Nsodium hydroxide. Then it was purified via reverse phase HPLC using 1liter of water followed by 5%˜25% acetonitrile and water. Water was thenremoved through concentrate in vacuo and 100 mg of product wascollected. MP: >250° C.; ¹H-NMR(DMSO): [7.66 (s, 1H), 7.36 (s, 1H), 7.08(m, 5H), 6.87 (s, 1H), 6.85 (s, 1H), 4.37 (m, 2H), 4.29 (m, 2H, CH2),3.65 (m, 2H, CH2), 2.73 (m, 2H, CH2), 2.46 (m, 2H, CH2), 2.02 (m, 2H,CH2). MS: 491.1 (M+H).

Example 28 Preparation of(5R,6Z)-6-(2,3-dihydro[1,3]thiazolo[3.2-a]benzimidazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0862] Step 1: Preparation of(2,3-Dihydro-benzo[4,5]imidazo[2,1-b]thiazol-7-yl)-methanol

[0863] To a round bottomed flask was added 2.83 grams of2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester,2.55 grams of dibromoethane and 50 ml DMF and 50 ml ethanol. The mixturewas refluxed for 10 hours. Then it was concentrated to dry on a rotaryevaporator. The solid was next dissolved in 100 ml THF and 20 ml of 1 MLiAlH₄ (in THF) was next injected within five minutes. The reactionmedia was stirred at room temperature for one hour. Ethanol was nextadded (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer was adjustedto basic Ph=14 with 10N sodium hydroxide. The aqueous was extracted with2×500 ml ethyl acetate. The combined organic layers was dried overmagnesium sulfate. Filter off the drying agent and cocentrate yielded2.04 grams (60%) product. MS: 207.0 (M+H). H-NMR(DMSO): □ 7.34 (m, 2H),7.08 (m, 1H), 5.15 (m, 1H, OH), 4.53 (m, 2H, CH2), 4.34 (m, 2H, CH2),4.00 (m, 2H, CH2).

[0864] Step 2: Preparation of2,3-Dihydro-benzo[4,5]imidazo[2,1-b]thiazole-7-carbaldehyde

[0865] To a pre-cooled (−50˜−60° C.) mixture of 1.7 ml DMSO and 5 mldichloromathane was injected a 20 ml dichloromethane solution of 1 mloxallyl chloride within five minutes. The mixture was stirred foranother five minutes at the same temperature. Then 1.9 grams of2,3-Dihydro-benzo[4,5]imidazo[2,1-b]thiazol-7-yl)-methanol in a mixtureof 20 ml dichloromethane and 20 ml THF was injected within 2 minutes.The mixture was kept stirred at −50˜−60° C. for 15 minutes. Then 7 mltriethylamine was injected all at once and after another 5 minutes thecooling bath was removed and the reaction was warmed up to roomtemperature by itself. Water (100 ml) was next added and the reactionmedia was extracted with 2×200 ml ethyl acetate. The combined organiclayers was dried over magnesium sulfate. Filter off the drying agent andconcentrate gave 1.2 grams product (64%). MS: 205.0 (M+H). H-NMR(CDCl3):□ 9.98 (m, 1H), 7.67 (m, 2H), 7.17 (m, 1H), 4.33 (m, 2H), 3.99 (m, 2H,CH2).

[0866] Step 3: Preparation of6-[Acetoxy-(2,3-dihydro-benzo[4,5]imidazo[2,1-b]thiazol-6-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicAcid 4-nitro-benzyl Ester

[0867] A 30 ml acetonitrile solution of2,3-Dihydro-benzo[4,5]imidazo[2,1-b]thiazole-7-carbaldehyde (610 mg, 2mmol) was added 1.03 gram of magnesium bromide etherate. The mixture wasstirred at 23° C. for half an hour. Then a 30 ml dry THF solution of the6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid4-nitro-benzyl ester (770 mg, 2 mmol) was injected within a minute andthe reaction mixture was then cooled to −20° C. Triethylamine (0.7 ml,eq.) was then injected and the reaction mixture was stirred for fivehours at −20° C. Then acetic anhydride (0.377 ml, eq.) was injected andthe reaction mixture was left at zero degree for 18 hours. The reactionmedia was then diluted with 400 ml ethyl acetate and washed with 100 ml5% citric acid, 100 ml saturated sodium bicarbonate, and 100 ml brine.The organic layer was then dried over magnesium sulfate, filtered andconcentrated. Flash column chromatography using 20% ethyl acetate inhexane gave 690 mg product. (54% Yield); MS: 630.8 (M+H)

[0868] Step 4: Preparation of(5R,6Z)-6-(2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0869]6-[Acetoxy-(2,3-dihydro-benzo[4,5]imidazo[2,1-b]thiazol-6-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (690 mg, 1.1 mmol) was suspended in 20 ml THFand 20 ml pH=6.5 aqueous phosphate buffer. The mixture was thensubjected to 45 psi hydrogen for two hours. Then it was filtered througha pad of celite and concentrated in vacuo to remove most of the THF. Thesolution was then cooled to zero degree and basified to pH=8 with 1 Nsodium hydroxide. Then it was purified via reverse phase HPLC using 1liter of water followed by 5%-25% acetonitrile and water. Water was thenremoved through concentrate in vacuo and 32 mg of product (Yield 3%) wascollected. MP: >250° C.; H-NMR(D₂O): □ 7.08 (m, 6H), 7.36 (s, 1H), 4.05(m, 2H), 3.90 (b, 1H); MS: 358.3 (M+H).

Example 29

[0870] Preparation of(5R,6Z)-6-(3.4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0871] Step 1: Preparation of(3.4-Dihydro-2H-1-thia-4a,9-diaza-fluoren-6-yl)-methanol

[0872] To a round bottomed flask was added 4.06 grams of2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester,4.04 grams of 1,3-dibromopropane and 50 ml DMF and 50 ml ethanol. Themixture was refluxed for 10 hours. Then it was concentrated to dry on arotary evaporator. The solid was next dissolved in 100 ml THF and 20 mlof 1M LiAlH₄ (in THF) was next injected within five minutes. Thereaction media was stirred at room temperature for one hour. Ethanol wasnext added (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer wasadjusted to basic Ph=14 with 10N sodium hydroxide. The aqueous wasextracted with 2×500 ml ethyl acetate. The combined organic layers wasdried over magnesium sulfate. Filter off the drying agent and cocentrateyielded 3 grams (68%) product. NMR(DMSO): δ 7.91 (m, 3H), 4.13 (m, 2H),3.93 (s, 1H), 3.23 (m, 2H, CH2), 2.48 (m, 2H, CH2). MS: 221.0 (M+H).

[0873] Step 2: Preparation of3.4-Dihydro-2H-1-thia-4a,9-diaza-fluorene-6-carbaldehyde

[0874] To a round bottomed flask was loaded 1.1 grams of(3,4-Dihydro-2H-1-thia-4a,9-diaza-fluoren-6-yl)-methanol, 6 grams ofmanganese dioxide and 250 ml chloroform. The mixture was stirred for onehour at room temperature and then filtered through a pad of celite. Thisyielded 0.67 grams of product (61%). MS: 219.0 (M+H). H-NMR(CDCl3): δ10.04 (s, 1H), 7.67 (m, 3H), 4.25 (m, 2H), 3.27 (m, 2H), 2.50 (m, 2H).

[0875] Step 3: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)(3.4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[0876] A 30 ml acetonitrile solution of3,4-Dihydro-2H-1-thia-4a,9-diaza-fluorene-6-carbaldehyde (660 mg, 3mmol) was added 1.03 gram of magnesium bromide etherate. The mixture wasstirred at 23° C. for half an hour. Then a 30 ml dry THF solution of the6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid4-nitro-benzyl ester (1.15 g, 3 mmol) was injected within a minute andthe reaction mixture was then cooled to −20° C. Triethylamine (0.7 ml,eq.) was then injected and the reaction mixture was stirred for fivehours at −20° C. Then acetic anhydride (0.377 ml, eq.) was injected andthe reaction mixture was left at zero degree for 18 hours. The reactionmedia was then diluted with 400 ml ethyl acetate and washed with 100 ml5% citric acid, 100 ml saturated sodium bicarbonate, and 100 ml brine.The organic layer was then dried over magnesium sulfate, filtered andconcentrated. Flash column chromatography using 20% ethyl acetate inhexane gave 690 mg product. (36% Yield); MS: 644.9 (M+H)

[0877] Step 4: Preparation of(5R,6Z)-6-(3.4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0878] 4-nitrobenzyl(5R)-6-[(acetyloxy)(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(700 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueousphosphate buffer. The mixture was then subjected to 45 psi hydrogen fortwo hours. Then it was filtered through a pad of celite and concentratedin vacuo to remove most of the THF. The solution was then cooled to zerodegree and basified to pH=8 with 1 N sodium hydroxide. Then it waspurified via reverse phase HPLC using 1 liter of water followed by5%-25% acetonitrile and water. Water was then removed throughconcentrate in vacuo and 75 mg of product (Yield 18%) was collected.MP: >250° C.; H-NMR(D₂O): δ 7.08 (m, 6H), 3.70 (m, 2H), 4.05 (m, 2H),3.13 (m, 2H), 2.22 (m, 2H); MS: 372.1 (M+H).

Example 30 Preparation of(5R,6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0879] Step 1: Preparation ofBenzo[4,5]imidazo[2,1-b]thiazole-6-carboxylic Acid Methyl Ester

[0880] To a round bottomed flask was loaded with 3.3 grams of2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester,4.5 ml alpha-bromodiethylacetal, 50 ml DMF. The mixture was refluxed for10 hours. Then is was poured into 10% sat. sodium bicarbonate (100 ml)and extracted with 2×100 ml ethyl acetate. The combined organic layerswere dried over magnesium sulfate. Filter off the drying agent,concentrate to dry, flash column chromatography using 10-30% ethylacetate/hexane yielded 1.16 grams (32%) crude product. MS: 233.1 (M+H).H-NMR(DMSO): δ 7.78 (m, 5H), 2.04 (s, 3H, CH3).

[0881] Step 2: Preparation ofBenzo[4,5]imidazo[2,1-b]thiazole-6-carbaldehyde

[0882] To a round bottomed flask was loaded 1.16 grams of(3,4-Dihydro-2H-1-thia-4a,9-diaza-fluoren-6-yl)-methanol, 25 grams ofmanganese dioxide and 250 ml chloroform. The mixture was stirred for onehour at room temperature and then filtered through a pad of celite. Thisyielded 0.42 grams of product (42%). MS: 203.0 (M+H). H-NMR(CDCl3): δ10.10 (ss, 1H), 8.24 (ss, 1H), 7.85 (m, 3H), 6.96 (m, 1H).

[0883] Step 3: Preparation of 4-nitrobenzyl(5R)-6-[(acetyloxy)([1,3]thiazolo[3,2-a]benzimidazol-6-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[0884] A 30 ml acetonitrile solution ofbenzo[4,5]imidazo[2,1-b]thiazole-6-carbaldehyde (404 mg, 2 mmol) wasadded 1.03 gram of magnesium bromide etherate. The mixture was stirredat 23° C. for half an hour. Then a 30 ml dry THF solution of the6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid4-nitro-benzyl ester (770 mg, 2 mmol) was injected within a minute andthe reaction mixture was then cooled to −20° C. Triethylamine (0.7 ml,eq.) was then injected and the reaction mixture was stirred for fivehours at −20° C. Then acetic anhydride (0.377 ml, eq.) was injected andthe reaction mixture was left at zero degree for 18 hours. The reactionmedia was then diluted with 400 ml ethyl acetate and washed with 100 ml5% citric acid, 100 ml saturated sodium bicarbonate, and 100 ml brine.The organic layer was then dried over magnesium sulfate, filtered andconcentrated. Flash column chromatography using 20% ethyl acetate inhexane gave 630 mg product. (50% Yield); MS: 631.9 (M+H)

[0885] Step 4: Preparation of(5R,6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid

[0886] 4-nitrobenzyl(5R)-6-[(acetyloxy)([1,3]thiazolo[3,2-a]benzimidazol-6-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(630 mg, 1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueousphosphate buffer. The mixture was then subjected to 45 psi hydrogen fortwo hours. Then it was filtered through a pad of celite and concentratedin vacuo to remove most of the THF. The solution was then cooled to zerodegree and basified to pH=8 with 1 N sodium hydroxide. Then it waspurified via reverse phase HPLC using 1 liter of water followed by5%-25% acetonitrile and water. Water was then removed throughconcentrate in vacuo and 33 mg of product (Yield 8%) was collected.MP: >250° C.; H-NMR(D₂O): δ 6.89 (m, 8H), 5.22 (s, 2H), 5.02 (s, 2H),4.81 (s, 2H). MS: 378.1 (M+H+Na).

Example 31 Preparation of(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0887] Step 1: Preparation ofethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)oxy]-1H-pyrazole-3-carboxylate:

[0888] To the stirred suspension of ethyl5-hydroxy-1H-pyrazole-3-carboxylate (7.0 g, 45 mmol) and 24.9 g g ofpotassium carbonate in 500 ml of acetonitrile was added 8.0 g of3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reactionmixture was allowed to cool to room temperature, then filtered, thesolid was washed with acetonitrile. The filtrate was concentrated to anoil. The residue was dissolved in ethyl acetate and extracted withwater. The organic phase was dried over MgSO₄ and evaporated to dryness.9.0 g (78%) of the desired product was obtained as a white solid. M.Pt.121-123° C.; (M+H) 255.

[0889] Step 2: Preparation of ethyl7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazole-2-carboxylate:

[0890] A mixture ofethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)oxy]-1H-pyrazole-3-carboxylate(254 mg, 1 mmol) and methane sulfonic acid (192 mg) in 7 ml of aceticacid and toluene (50 ml) was refluxed for 18 hours using a Dean-Starktrap to remove water. The reaction mixture was allowed to cool to roomtemperature. The reaction mixture was filtered. The filtrate wasconcentrated to an oil. The residue was dissolved in ethyl acetateaqueous bicarbonate solution. The organic layer was washed with waterand dried over MgSO₄. After removal of the ethyl acetate, the residuewas purified by silica gel chromatography eluting with ethylacetate/hexane to give 120 mg (51%) of the desired product as whitesolid. Mp; 116-118° C.; Electrospray-MS m/z 237.0 (M+H)⁺

[0891] Step 3: Preparation of7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethanol:

[0892] To the stirred solution of7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazole-2-carboxylate(1.5 g, 6.3 mmol) of in 100 ml of THF was added 1.05 g of lithiumborohydride and 1.54 g of methanol. The solution was heated at 4° C. for2.5 hour. The reaction was quenched by 1N HCl, and adjusted to pH 1.3and stirred at room temperature for 1 hour. The reaction mixture wasadjusted pH to 8 with k₂CO₃. The reaction mixture was extracted withethyl acetate. The organic layer was dried over MgSO₄, and concentratedto an oil and column chromatographyed to give 0.74 g of the desiredproduct (60%). (M+H) 196.

[0893] Step 4: Preparation of7,8-dihydro-5H-pyrano[4.3-d]pyrazolo[5,1-b][1,3]oxazol-2-carbaldehyde:

[0894] To the stirred solution of7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethanol (1.0g, 5.1 mmol) in 60 ml of CHCl₃ was added 8 g of MnO₂. Th suspension wasrefluxed for 1.5 hour under a nitrogen atmosphere. The reaction mixturewas filtered through a pad of Celite. The filtrate was concentrated togive yellow oil. The product was purified by chromatography. 0.79 g ofthe product was obtained (80%); (M+H) 193

[0895] Step 5: 4-Nitrobenzy(5R)-6-[(acetyloxy)(7,8-dihydro-5H-pyrano[4,3]pyrazolo[5,1-b][1,3]oxazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[0896]7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-carbaldehyde(600 mg, 3.1 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.54 g, 4.6 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (2.21g, 8.5 mmol)under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereo isomers were taken to nextstep. Pale yellow amorphous solid; Yield: 1.35 g, 70%; (M+H) 619.

[0897] Step 6: Preparation of(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt &(5R,6E)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0898] 4-Nitrobenzy(5R)-6-[(acetyloxy)(7,8-dihydro-5H-pyrano[4,3]pyrazolo[5,1-b][1,3]oxazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.2 g, 1.9 mmol) was dissolved in THF (20 mL), acetonitrile (10 mL) and0.5 M phosphate buffer (pH 6.5, 28 mL) and hydrogenated over 10% Pd/C at40 psi pressure. After 4 hrs the reaction mixture was filtered, cooledto 3° C., and 0.1 M NaOH was added to adjust pH to 8.5. The filtrate waswashed with ethyl acetate and the aqueous layer was separated. Theaqueous layer was concentrated under high vacuum at 35° C. to giveyellow precipitate. The product was purified by HP21 resin reverse phasecolumn chromatography. Initially the column was eluted with deionizedwater (2 lits) and latter with 10% acetonitrile: Water. The fractionscontaining the product were collected and concentrated at reducedpressure at room temperature. The yellow solid was washed with acetoneand filtered. In this reaction both E and Z isomers were formed and theywere separated by prep. HPLC.(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt: Yield 87 mg, (25%); Yellow solid; (M+H+Na) 368.2.

[0899] H-NMR (D₂O): 7.04 (1H, s), 7.01 (1H, s), 6.45 (1H, s), 6.09 (1H,s), 4.76 (2H, m), 4.12 (2H, m), 2.96 (2H, m).

[0900](5R,6E)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt: Yield 75 mg, (21%); Yellow solid; (M+H+Na) 368.2.

[0901] H-NMR (D₂O): 7.08 (1H, s), 6.81 (1H, s), 6.71 (1H, s), 6.40 (1H,s), 4.68 (2H, m), 4.03 (2H, m), 2.87 (2H, m).

Example 32 Preparation of(5R,6Z)-7-oxo-6-(5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0902] Step 1: Preparation ofethyl-5-[(2-oxocyclohexyl)oxy]-1H-pyrazole-3-carboxylate:

[0903] To the stirred suspension of ethyl5-hydroxy-1H-pyrazole-3-carboxylate (6.25 g, 40 mmol) and 22.1 g ofpotassium carbonate in 500 ml of acetonitrile was added 6.35 g of2-chlorocyclohexanone, and refluxed for 16 hours. The reaction mixturewas allowed to cool to room temperature, then filtered, the solid waswashed with acetonitrile. The filtrate was concentrated to an oil. Theresidue was dissolved in ethyl acetate and extracted with water. Theorganic phase was dried over MgSO₄ and evaporated to dryness. Theproduct was purified by silics-gel column chromatography by eluting itwith 1:1 ethyl acetaet;hexane. 4.92 g (49%) of the desired product wasobtained as a white solid. M.Pt. 122-124° C.; (M+H) 253.

[0904] Step 2: Preparation of Ethyl5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole-2-carboxylate:

[0905] A mixture ofethyl-5-[(2-oxocyclohexyl)oxy]-1H-pyrazole-3-carboxylate (127.6 mg, 0.5mmol) and methane sulfonic acid (95 mg) in 5 ml of acetic acid andtoluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap toremove water. The reaction mixture was allowed to cool to roomtemperature. The reaction mixture was filtered. The filtrate wasconcentrated to an oil. The residue was dissolved in ethyl acetate andaqueous bicarbonate solution. The organic layer was washed with waterand dried over MgSO₄. After removal of the ethyl acetate, the residuewas purified by silica gel chromatography eluting with 1:1 ethylacetate/hexane to give 69.7 mg (59%) of the desired product as whitesolid. Mp; 55-57° C.; Electrospray-MS m/z 235.0 (M+H)⁺

[0906] Step 3: Preparation of5,6,7,8-tetraihydropyrazolo[5,1-b][1,3]benzoxazol-2-ylmethanol:

[0907] To the stirred solution of ethyl5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole-2-carboxylate (3.84 g,16.4 mmol) of in 100 ml of THF was added 3.05 g of lithium borohydrideand 3 ml of methanol. The solution was heated at 4° C. for 2.5 hour. Thereaction was quenched by 1 N HCl, and adjusted to pH 1.3 and stirred atroom temperature for 1 hour. The reaction mixture was adjusted pH to 8with k₂CO₃. The reaction mixture was extracted with ethyl acetate. Theorganic layer was dried over MgSO₄, and concentrated to an oil andcolumn chromatographyed to give 2.62 g of the desired product (83%).Mpt. 82-84° C.; (M+H) 193.

[0908] Step 4: Preparation of5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole-2-carbaldehyde:

[0909] To the stirred solution of5,6,7,8-tetraihydropyrazolo[5,1-b][1,3]benzoxazol-2-ylmethanol (2.30 g,11.97 mmol) in 60 ml of CHCl₃ was added 10 g of MnO₂. Th suspension wasrefluxed for 1.5 hour under a nitrogen atmosphere. The reaction mixturewas filtered through a pad of Celite. The filtrate was concentrated togive yellow solid. The product was purified by chromatography. 1.95 g ofthe product was obtained (85.5%); (M+H) 191

[0910] Step 5: 4-Nitrobenzy(5R)-6-[(acetyloxy)(5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazol-2-yl)methyl-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[0911] 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole-2-carbaldehyde(589 mg, 3.1 mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.54 g, 4.6 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (2.21g, 8.5 mmol)under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereo isomers were taken to nextstep. Pale yellow amorphous solid; Yield: 792 mg, 42%; M.pt. 160-162°C.; (M+H) 618.

[0912] Step 6: Preparation of(5R,6Z)-7-oxo-6-(5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0913] 4-Nitrobenzy(5R)-6-[(acetyloxy)(5,67,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazol-2-yl)methyl-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(318 mg, 0.5 mmol) was dissolved in THF (20 mL), acetonitrile (10 mL)and 0.5 M phosphate buffer (pH 6.5, 28 mL) and hydrogenated over 10%Pd/C (100 mg) at 40 psi pressure. After 4 hrs the reaction mixture wasfiltered, cooled to 3° C., and 0.1 M NaOH was added to adjust pH to 8.5.The filtrate was washed with ethyl acetate and the aqueous layer wasseparated. The aqueous layer was concentrated under high vacuum at 35°C. to give yellow precipitate. The product was purified by HP21 resinreverse phase column chromatography. Initially the column was elutedwith deionized water (2 lits) and latter with 10% acetonitrile: Water.The fractions containing the product were collected and concentrated atreduced pressure at room temperature. The yellow solid was washed withacetone and filtered. Yield 150 mg, (76%); Yellow solid; (M+H+Na) 365.2.

[0914] H-NMR (D₂O): δ 6.92 (1H, s), 6.91 (1H, s), 6.32 (1H, s), 5.85(1H, s), 2.59 (4H, m), 1.80 (4H, m).

Example 33 Preparation of(5R,6Z)-6-([6-(ethoxycarbonyl)-5,6,7,8-tetrahydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0915] Step 1: Preparation of ethyl3-{[3-ethoxycarbonyl)-1H-pyrazol-5-yl]oxy}-4-oxopiperidine-1-carboxylate:

[0916] To the stirred suspension of ethyl5-hydroxy-1H-pyrazole-3-carboxylate (19.5 g, 127 mmol) and 50.0 g ofpotassium carbonate in 500 ml of acetonitrile was added3-bromo-4-oxo-piperidine-1-carboxylic acid ethyl ester (37.45 g, 149mmol), and refluxed for 16 hours. The reaction mixture was allowed tocool to room temperature, then filtered, the solid was washed withacetonitrile. The filtrate was concentrated to an oil. The residue wasdissolved in ethyl acetate and extracted with water. The organic phasewas dried over MgSO₄ and evaporated to dryness. The product was purifiedby silics-gel column chromatography by eluting it with 1:1 ethylacetaet;hexane. 8.5 g (19%) of the desired product was obtained as anyellow oil. (M+H) 326.

[0917] Step 2: Preparation of Diethyl 7,8-tetrahydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-2,6(5H)-dicarboxylate:

[0918] A mixture of ethyl3-{[3-ethoxycarbonyl)-1H-pyrazol-5-yl]oxy}-4-oxopiperidine-1-carboxylate(325 mg, 1 mmol) and methane sulfonic acid (95 mg) in 5 ml of aceticacid and toluene (50 ml) was refluxed for 18 hours using a Dean-Starktrap to remove water. The reaction mixture was allowed to cool to roomtemperature. The reaction mixture was filtered. The filtrate wasconcentrated to an oil. The residue was dissolved in ethyl acetate andaqueous bicarbonate solution. The organic layer was washed with waterand dried over MgSO₄. After removal of the ethyl acetate, the residuewas purified by silica gel chromatography eluting with 1:1 ethylacetate/hexane to give 175 mg (57%) of the desired product as an yellowoil Electrospray-MS m/z 308.0 (M+H)⁺

[0919] Step 3: Preparation of ethyl2-(hydroxymethyl)-7,8-dihydropyrazolo [5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate

[0920] To the stirred solution of diethyl7,8-tetrahydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-2,6(5H)-dicarboxylate(307 mg, 1 mmol) of in 40 ml of THF was added 305 mg of lithiumborohydride and 1 ml of methanol. The solution was heated at 4° C. for2.5 hour. The reaction was quenched by 1 N HCl, and adjusted to pH 1.3and stirred at room temperature for 1 hour. The reaction mixture wasadjusted pH to 8 with k₂CO₃. The reaction mixture was extracted withethyl acetate. The organic layer was dried over MgSO₄, and concentratedto an oil and column chromatographyed to give 172 mg of the desiredproduct (65%); (M+H) 266.

[0921] Step 4: Preparation of ethyl 2-formyl-7,8-dihydropyrazolo [5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate

[0922] To the stirred solution of ethyl2-(hydroxymethyl)-7,8-dihydropyrazolo [5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate (1.76 g, 6.6 mmol)in 60 ml of CHCl₃ was added 10 g of MnO₂. Th suspension was refluxed for1.5 hour under a nitrogen atmosphere. The reaction mixture was filteredthrough a pad of Celite. The filtrate was concentrated to give yellowsolid. The product was purified by chromatography. 1.43 g of the productwas obtained (82%); M.pt: 97-99° C. (M+H) 264.

[0923] Step 5: Preparation of ethyl2-[(acetyloxy)(5R)-6-bromo-2-Z{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-6-yl)methyl]-7,8-dihydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylateEthyl2-formyl-7,8-dihydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate

[0924] (790 mg, 3. mmol) and the dry THF solution (20 mL) of (5R,6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid 4-nitro-benzyl ester (1.54 g, 4.6 mmol) were added successively tothe dry acetonitrile (15 mL) solution of anhydrous MgBr₂: O(Et)₂ (2.21g, 8.5 mmol)under an argon atmosphere at room temperature. After coolingto −20° C., Et₃N (2.0 mL) was added in one portion. The reaction vesselwas covered with foil to exclude light. The reaction mixture was stirredfor 2 h at −20° C. and treated with acetic anhydride (1.04 mL) in oneportion. The reaction mixture was warmed to 0° C. and stirred for 15 hat 0° C. The mixture was diluted with ethyl acetate and washed with 5%citric acid aqueous solution, saturated sodium hydrogen carbonate, andbrine. The organic layer was dried (MgSO₄) and filtered through a pad ofCelite. The pad was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure. The residue was applied to silicagel column chromatography, then the column was eluted with ethylacetate:hexane (1:1). Collected fractions were concentrated underreduced pressure and the mixture of diastereo isomers were taken to nextstep. Pale yellow amorphous solid; Yield: 1.67 g, 81%; (M+H) 690.

[0925] Step 6: Preparation of(5R,6Z)-6-{[6-(ethoxycarbonyl)-5,6,7,8-tetrahydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicAcid, Sodium Salt

[0926] Ethyl2-[(acetyloxy)(5R)-6-bromo-2-Z{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-6-yl)methyl]-7,8-dihydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate(828 mg, 0.5 mmol) was dissolved in THF (20 mL), acetonitrile (10 mL)and 0.5 M phosphate buffer (pH 6.5, 28 mL) and hydrogenated over 10%Pd/C (200 mg) at 40 psi pressure. After 4 hrs the reaction mixture wasfiltered, cooled to 3° C., and 0.1 M NaOH was added to adjust pH to 8.5.The filtrate was washed with ethyl acetate and the aqueous layer wasseparated. The aqueous layer was concentrated under high vacuum at 35°C. to give yellow precipitate. The product was purified by HP21 resinreverse phase column chromatography. Initially the column was elutedwith deionized water (2 lits) and latter with 10% acetonitrile: Water.The fractions containing the product were collected and concentrated atreduced pressure at room temperature. The yellow solid was washed withacetone and filtered. Yield 375 mg, (71%); Yellow solid; (M+H+Na) 438.4.

[0927] H-NMR (D₂O): δ 6.96 (1H, s), 6.94 (1H, s), 6.41 (1H, s), 6.00(1H, s), 4.53 (2H, m), 4.13 (2H, q), 3.78 (2H, m), 2.78 (2H, m), 1.21(3H, t).

What is claimed is:
 1. A compound of formula I

wherein: one of A and B denotes hydrogen and the other an optionallysubstituted fused tricyclic heteroaryl group; X is S or O; R₅ is H,C1-C6 alkyl, C5-C6 cycloalkyl, or CHR₃OCOC1-C6alkyl; and R₃ is hydrogen,C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; or a pharmaceutically acceptable saltor in vivo hydrolysable ester thereof.
 2. The compound according toclaim 1 wherein the tricyclic heteroarylgroup has the formula

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ are independently CR₂, N, O, S orN—R₁ provided one of Z₁-Z₇ is a carbon atom to which the remainder ofthe molecule is attached; R₁ is H, optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl or monoor bicyclic saturated heterocycles, optionally substituted cycloalkyl,optionally substituted alkenyl, optionally substituted alkynyl with theproviso that neither the double bond nor the triple bond should bepresent at the carbon atom which is directly linked to N; optionallysubstituted perfluoroalkyl, —S(O)_(p) optionally substituted alkyl oraryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionallysubstituted —C═Oaryl, optionally substituted —C═Oalkyl, optionallysubstituted —C═Ocycloalkyl, optionally substituted —C═O mono or bicyclicsaturated heterocycles, optionally substituted C1-C6 alkylaryl,optionally substituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ may independently be C or N. 3.The compound according to claim 1 wherein the tricyclic heteroaryl groupis

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ and Z₈ are independently CR₂, N, O, Sor N—R₁ provided one of the Z₁-Z₈ is a carbon atom to which theremainder of the molecule is attached; R₁ is H, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl ormono or bicyclic saturated heterocycles, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl with the proviso that neither the double bond nor the triplebond should be present at the carbon atom which is directly linked to N;optionally substituted perfluoroalkyl, —S(O)_(p) optionally substitutedalkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl,optionally substituted —C═Oaryl, optionally substituted —C═Oalkyl,optionally substituted —C═Ocycloalkyl, optionally substituted —C═O monoor bicyclic saturated heterocycles, optionally substituted C1-C6alkylaryl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 4. Thecompound according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z, Z₅, Z₆, Z₇ and Z₈ are independently CR₂, N, O, Sor N—R₁ provided one of Z₁-Z₈ is a carbon atom to which the remainder ofthe molecule is attached; R₁ is H, optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl or monoor bicyclic saturated heterocycles, optionally substituted cycloalkyl,optionally substituted alkenyl, optionally substituted alkynyl with theproviso that neither the double bond nor the triple bond should bepresent at the carbon atom which is directly linked to N; optionallysubstituted perfluoroalkyl, —S(O)_(p) optionally substituted alkyl oraryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionallysubstituted —C═Oaryl, optionally substituted —C═Oalkyl, optionallysubstituted —C═Ocycloalkyl, optionally substituted —C═O mono or bicyclicsaturated heterocycles, optionally substituted C1-C6 alkylaryl,optionally substituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ may be C or N.
 5. The compoundaccording to claim 1 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z, Z₅, Z₆, Z₇, Z₈ and Z₉ are independently CR₂, N,O, S or N—R₁ provided one of the Z₁-Z₉ is a carbon atom to which theremainder of the molecule is attached; R₁ is H, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl ormono or bicyclic saturated heterocycles, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl with the proviso that neither the double bond nor the triplebond should be present at the carbon atom which is directly linked to N;optionally substituted perfluoroalkyl, —S(O)_(p) optionally substitutedalkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl,optionally substituted —C═Oaryl, optionally substituted —C═Oalkyl,optionally substituted —C═Ocycloalkyl, optionally substituted —C═O monoor bicyclic saturated heterocycles, optionally substituted C1-C6alkylaryl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 6. Thecompound according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃ and Z₄ are independently CR₂, N, O, S or N—R₁provided one of Z₁-Z₄ is a carbon atom to which the remainder of themolecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N; W₁, W₂and W₃ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 3. 7. The compound according to claim 1wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄ and Z₅ are independently CR₂, N, O, S or N—R₁provided one of Z₁-Z₅ is a carbon atom to which the remainder of themolecule is attached; Y₁ and Y₂ are independently C or N; W₁, W₂ and W₃are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring; R₁is H, optionally substituted alkyl, optionally substituted aryl,optionally substituted heteroaryl or mono or bicyclic saturatedheterocycles, optionally substituted cycloalkyl, optionally substitutedalkenyl, optionally substituted alkynyl with the proviso that neitherthe double bond nor the triple bond should be present at the carbon atomwhich is directly linked to N; optionally substituted perfluoroalkyl,—S(O)_(p) optionally substituted alkyl or aryl where p is 0-2,optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl,optionally substituted —C═Oalkyl, optionally substituted —C═Ocycloalkyl,optionally substituted —C═O mono or bicyclic saturated heterocycles,optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6alkylheteroaryl, optionally substituted aryl-C1-C6alkyl, optionallysubstituted heteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionallysubstituted arylalkyloxyalkyl, optionally substituted-alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, optionally substitutedC1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 3. 8. The compound according to claim 1wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ are independently CR₂, N, O, S, andN—R₁; provided one of Z₁-Z₆ is a carbon atom to which the remainder ofthe molecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N; W₁and W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; R₁ is H, optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl or mono or bicyclic saturatedheterocycles, optionally substituted cycloalkyl, optionally substitutedalkenyl, optionally substituted alkynyl with the proviso that neitherthe double bond nor the triple bond should be present at the carbon atomwhich is directly linked to N; optionally substituted perfluoroalkyl,—S(O)_(p) optionally substituted alkyl or aryl where p is 0-2,optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl,optionally substituted —C═Oalkyl, optionally substituted —C═Ocycloalkyl,optionally substituted —C═O mono or bicyclic saturated heterocycles,optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6alkylheteroaryl, optionally substituted aryl-C1-C6alkyl, optionallysubstituted heteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionallysubstituted arylalkyloxyalkyl, optionally substituted-alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, optionally substitutedC1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 3. 9. The compound according to claim 1wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ are indepdently CR₂, N, O, S orN—R₁ provided one of the Z₁-Z₇ is a carbon atom to which the remainderof the molecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N;W₁ and W₂ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=0-3.
 10. The compound according to claim 1 whereinthe tricyclic heteroaryl group is

wherein Z₁, Z₂ and Z₃ are independently CR₂ N, O, S or N—R₁ provided oneof Z₁-Z₃ is a carbon atom to which the remainder of the molecule isattached; Y₁ and Y₄ are independently C or N; Y₂ and Y₃ areindependently CH or N; W₁, W₂ W₃, W₄ and W₅ are independently CR₄R₄,S(O)r (r=0-2), O, or N—R₁ with the proviso that no S—S, S—O or O—O bondformation can occur to form a saturated ring; R₁ is H, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl or mono or bicyclic saturated heterocycles, optionallysubstituted cycloalkyl, optionally substituted alkenyl, optionallysubstituted alkynyl with the proviso that neither the double bond northe triple bond should be present at the carbon atom which is directlylinked to N; optionally substituted perfluoroalkyl, —S(O)_(p) optionallysubstituted alkyl or aryl where p is 0-2, optionally substituted—C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted—C═Oalkyl, optionally substituted —C═Ocycloalkyl, optionally substituted—C═O mono or bicyclic saturated heterocycles, optionally substitutedC1-C6 alkylaryl, optionally substituted C1-C6 alkylheteroaryl,optionally substituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; t=0 to 2; and u=1 to
 3. 11. The compound according toclaim 1 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ and Z₉ are independently CR₂, N,O, S or N—R₁ provided one of the Z₁-Z₉ is a carbon atom to which theremainder of the molecule is attached; R₁ is H, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl ormono or bicyclic saturated heterocycles, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl with the proviso that neither the double bond nor the triplebond should be present at the carbon atom which is directly linked to N;optionally substituted perfluoroalkyl, —S(O)_(p) optionally substitutedalkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl,optionally substituted —C═Oaryl, optionally substituted —C═Oalkyl,optionally substituted —C═Ocycloalkyl, optionally substituted —C═O monoor bicyclic saturated heterocycles, optionally substituted C1-C6alkylaryl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 12. Thecompound according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈, Z₉ and Z₁₀ are independentlyCR₂, N, O, S or N—R₁ provided one of Z₁-Z₁₀ is a carbon atom to whichthe remainder of the molecule is attached; R₁ is H, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl or mono or bicyclic saturated heterocycles, optionallysubstituted cycloalkyl, optionally substituted alkenyl, optionallysubstituted alkynyl with the proviso that neither the double bond northe triple bond should be present at the carbon atom which is directlylinked to N; optionally substituted perfluoroalkyl, —S(O)_(p) optionallysubstituted alkyl or aryl where p is 0-2, optionally substituted—C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted—C═Oalkyl, optionally substituted —C═Ocycloalkyl, optionally substituted—C═O mono or bicyclic saturated heterocycles, optionally substitutedC1-C6 alkylaryl, optionally substituted C1-C6 alkylheteroaryl,optionally substituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 13. Thecompound according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄ and Z₅ are independently CR₂, N, O, S or N—R₁provided that one of Z₁-Z₅ is a carbon atom to which the remainder ofthe molecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N;W₁, W₂, W₃ are independently CR₄R₄ O, N—R₁, or S═(O)_(r) (r=0-2) withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R4 are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1-4.
 14. The compound according to claim 1 whereinthe tricyclic heteroaryl group is

wherein Z₁, Z₂ Z₃, Z₄, Z₅ and Z₆ are independently CR₂, N, O, S or N—R₁provided one of Z₁-Z₆ is a carbon atom to which the remainder of themolecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N; W₁, W₂and W₃ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 3. 15. The compound according to claim 1wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ and Z₈ are independently CR₂, N, O, Sor N—R₁ provided one of Z₁-Z₈ is a carbon atom to which the remainder ofthe molecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N;W₁, and W₂ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R4 are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 2. 16. The compound according to claim 1wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃ and Z₄ are independently CR₂, N, O, S or N—R₁provided one of Z₁-Z₄ is a carbon atom to which the remainder of themolecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N; W₁,W₂, W₃, W₄ and W₅ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R4 are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; t=1 to 3; and u=1 to
 3. 17. The compound according toclaim 1 wherein the compound has the formula

and wherein X is S.
 18. The compound according to claim 1 wherein X isS.
 19. The compound according to claim 1 selected from the groupconsisting of a.(5R,6Z)-6-(Imidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; b.(5R,6Z)-6-[(7-methoxyimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; c.(5R,6Z)-6-[(7-chloroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; d. (5R),(6Z)-6-Imidazo[1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; e. (5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; f. (5R),(6Z)-6-(Imidazo[1.2-a]quinoxaline-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hepto-2-ene-2-carboxylicacid, sodium salt; g.(5R,6Z)-6-[(7-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; h. (5R),(6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid sodium salt; i.(5R,6E)-6-[(10-benzyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-8-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; j.6-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid; k. (5R,6E&Z)-7-oxo-6-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; l. (5R),(6Z)-6-(5H-Imidazo[2,1-a]isoindol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid sodium salt; m.(5R,6Z)-6-[(5-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; n.(5R,6Z)-6-[(7-fluoroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; o. (5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; p. (5R),(6Z)-6-(imidazo[2,1-b]bebzothiazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; q. (5R),(6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; r. (5R),(6Z)-6-(7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-6-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; s. (5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; t.(5R),(6Z)-8-[(9-methyl-9H-imidazo[1,2-a]benzimidazol-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; u. (5R,6Z)-7-oxo-6-(4H-thieno[2′,3′:4,5]thiopyrano[2,3-b]pyridin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid (Sodium salt); v.(5R,6Z)-6-[(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; w.(5R,6Z)-6-{[7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; x.(5R,6Z)-6-(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolo[1,5-a]quinazolin]-2′-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; y.(5R,6Z)-6-[(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; z.(5R,6Z)-6-[(5-methoxy-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; aa.(5R,6Z)-6-({5-[2-(benzyloxy)ethoxy]-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl}methylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; bb.(5R,6Z)-6-(2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; cc.(5R,6Z)-6-(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; dd.(5R,6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; ee.(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; ff.(5R,6Z)-7-oxo-6-(5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; and gg.(5R,6Z)-6-{[6-(ethoxycarbonyl)-5,6,7,8-tetrahydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt.
 20. The compound according to claim 19 selected fromthe group consisting of (5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; and (5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
 21. The compoundaccording to claim 20,(5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid.
 22. A method for the treatment of bacterial infection or diseasein a patient in need thereof which comprises providing to said patientan effective amount of a compound of formula I:

wherein: one of A and B denotes hydrogen and the other an optionallysubstituted fused tricyclic heteroaryl group; X is S or O; R₅ is H,C1-C6 alkyl, C5-C6 cycloalkyl, or CHR₃OCOC1-C6alkyl; and R₃ is hydrogen,C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; or a pharmaceutically acceptable saltor in vivo hydrolysable ester thereof.
 23. The method according to claim22 wherein the compound is co-administered with a betalactam antibiotic.24. The method according to claim 22 wherein the ratio of β-lactamantibiotic to the compound is in a range from about 1:1 to 100:1. 25.The method according to claim 24 wherein the ratio of the β-lactamantibiotic to the compound is less than 10:1.
 26. The method accordingto claim 22 wherein the tricyclic heteroarylgroup has the formula

wherein Z₁, Z₂, Z₃, Z₄ Z₅, Z₆ and Z₇ are independently CR₂; N, O, S orN—R₁ provided one of Z₁-Z₇ is a carbon atom to which the remainder ofthe molecule is attached; R₁ is H, optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl or monoor bicyclic saturated heterocycles, optionally substituted cycloalkyl,optionally substituted alkenyl, optionally substituted alkynyl with theproviso that neither the double bond nor the triple bond should bepresent at the carbon atom which is directly linked to N; optionallysubstituted perfluoroalkyl, —S(O)_(p) optionally substituted alkyl oraryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionallysubstituted —C═Oaryl, optionally substituted —C═Oalkyl, optionallysubstituted —C═Ocycloalkyl, optionally substituted —C═O mono or bicyclicsaturated heterocycles, optionally substituted C1-C6 alkylaryl,optionally substituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ may independently be C or N. 27.The method according to claim 22 wherein the tricyclic heteroaryl groupis

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ and Z₈ are independently CR₂, N, O, Sor N—R₁ provided one of the Z₁-Z₈ is a carbon atom to which theremainder of the molecule is attached; R₁ is H, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl ormono or bicyclic saturated heterocycles, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl with the proviso that neither the double bond nor the triplebond should be present at the carbon atom which is directly linked to N;optionally substituted perfluoroalkyl, —S(O)_(p) optionally substitutedalkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl,optionally substituted —C═Oaryl, optionally substituted —C═Oalkyl,optionally substituted —C═Ocycloalkyl, optionally substituted —C═O monoor bicyclic saturated heterocycles, optionally substituted C1-C6alkylaryl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 28. Themethod according to claim 22 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ and Z₈ are independently CR₂, N, O, Sor N—R₁ provided one of Z₁-Z₈ is a carbon atom to which the remainder ofthe molecule is attached; R₁ is H, optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl or monoor bicyclic saturated heterocycles, optionally substituted cycloalkyl,optionally substituted alkenyl, optionally substituted alkynyl with theproviso that neither the double bond nor the triple bond should bepresent at the carbon atom which is directly linked to N; optionallysubstituted perfluoroalkyl, —S(O)_(p) optionally substituted alkyl oraryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionallysubstituted —C═Oaryl, optionally substituted —C═Oalkyl, optionallysubstituted —C═Ocycloalkyl, optionally substituted —C═O mono or bicyclicsaturated heterocycles, optionally substituted C1-C6 alkylaryl,optionally substituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 29. Themethod according to claim 22 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ and Z₉ are independently CR₂, N,O, S or N—R₁ provided one of the Z₁-Z₉ is a carbon atom to which theremainder of the molecule is attached; R₁ is H, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl ormono or bicyclic saturated heterocycles, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl with the proviso that neither the double bond nor the triplebond should be present at the carbon atom which is directly linked to N;optionally substituted perfluoroalkyl, —S(O)_(p) optionally substitutedalkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl,optionally substituted —C═Oaryl, optionally substituted —C═Oalkyl,optionally substituted —C═Ocycloalkyl, optionally substituted —C═O monoor bicyclic saturated heterocycles, optionally substituted C1-C6alkylaryl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 30. Themethod according to claim 22 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃ and Z₄ are independently CR₂, N, O, S or N—R₁provided one of Z₁-Z₄ is a carbon atom to which the remainder of themolecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N; W₁, W₂and W₃ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 3. 31. The method according to claim 22wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄ and Z₅ are independently CR₂, N, O, S or N—R₁provided one of Z₁-Z₅ is a carbon atom to which the remainder of themolecule is attached; Y₁, and Y₂ are independently C or N; W₁, W₂ and W₃are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with the proviso thatno S—S, S—O or O—O bond formation can occur to form a saturated ring; R₁is H, optionally substituted alkyl, optionally substituted aryl,optionally substituted heteroaryl or mono or bicyclic saturatedheterocycles, optionally substituted cycloalkyl, optionally substitutedalkenyl, optionally substituted alkynyl with the proviso that neitherthe double bond nor the triple bond should be present at the carbon atomwhich is directly linked to N; optionally substituted perfluoroalkyl,—S(O)_(p) optionally substituted alkyl or aryl where p is 0-2,optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl,optionally substituted —C═Oalkyl, optionally substituted —C═Ocycloalkyl,optionally substituted —C═O mono or bicyclic saturated heterocycles,optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6alkylheteroaryl, optionally substituted aryl-C1-C6alkyl, optionallysubstituted heteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionallysubstituted arylalkyloxyalkyl, optionally substituted-alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, optionally substitutedC1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 3. 32. The method according to claim 22wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ are independently CR₂, N, O, S, andN—R₁; provided one of Z₁-Z₆ is a carbon atom to which the remainder ofthe molecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N; W₁and W₂ are independently CR₄R₄, S(O)r (r=0-2), O, N—R₁ with the provisothat no S—S, S—O or O—O bond formation can occur to form a saturatedring; R₁ is H, optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl or mono or bicyclic saturatedheterocycles, optionally substituted cycloalkyl, optionally substitutedalkenyl, optionally substituted alkynyl with the proviso that neitherthe double bond nor the triple bond should be present at the carbon atomwhich is directly linked to N; optionally substituted perfluoroalkyl,—S(O)_(p) optionally substituted alkyl or aryl where p is 0-2,optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl,optionally substituted —C═Oalkyl, optionally substituted —C═Ocycloalkyl,optionally substituted —C═O mono or bicyclic saturated heterocycles,optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6alkylheteroaryl, optionally substituted aryl-C1-C6alkyl, optionallysubstituted heteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionallysubstituted arylalkyloxyalkyl, optionally substituted-alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, optionally substitutedC1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 3. 33. The method according to claim 22wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆ and Z₇ are indepdently CR₂, N. O, S orN—R₁ provided one of the Z₁-Z₇ is a carbon atom to which the remainderof the molecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N;W₁ and W₂ are independently CR₄R₄, S(O)r (r=0-2), N, or N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=0-3.
 34. The method according to claim 22 whereinthe tricyclic heteroaryl group is

wherein Z₁, Z₂ and Z₃ are independently CR₂ N, O, S or N—R₁ provided oneof Z₁-Z₃ is a carbon atom to which the remainder of the molecule isattached; Y₁ and Y₄ are independently C or N; Y₂ and Y₃ areindependently CH or N; W₁, W₂ W₃, W₄ and W₅ are independently CR₄R₄,S(O)r (r=0-2), O, or N—R₁ with the proviso that no S—S, S—O or O—O bondformation can occur to form a saturated ring; R₁ is H, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl or mono or bicyclic saturated heterocycles, optionallysubstituted cycloalkyl, optionally substituted alkenyl, optionallysubstituted alkynyl with the proviso that neither the double bond northe triple bond should be present at the carbon atom which is directlylinked to N; optionally substituted perfluoroalkyl, —S(O)_(p) optionallysubstituted alkyl or aryl where p is 0-2, optionally substituted—C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted—C═Oalkyl, optionally substituted —C═Ocycloalkyl, optionally substituted—C═O mono or bicyclic saturated heterocycles, optionally substitutedC1-C6 alkylaryl, optionally substituted C1-C6 alkylheteroaryl,optionally substituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; t=0 to 2; and u=1 to
 3. 35. The method according toclaim 22 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈ and Z₉ are independently CR₂, N,O, S or N—R₁ provided one of the Z₁— Z is a carbon atom to which theremainder of the molecule is attached; R₁ is H, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl ormono or bicyclic saturated heterocycles, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl with the proviso that neither the double bond nor the triplebond should be present at the carbon atom which is directly linked to N;optionally substituted perfluoroalkyl, —S(O)_(p) optionally substitutedalkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl,optionally substituted —C═Oaryl, optionally substituted —C═Oalkyl,optionally substituted —C═Ocycloalkyl, optionally substituted —C═O monoor bicyclic saturated heterocycles, optionally substituted C1-C6alkylaryl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 36. Themethod according to claim 22 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈, Z₉ and Z₁₀ are independentlyCR₂, N, O, S or N—R₁ provided one of Z₁-Z₁₀ is a carbon atom to whichthe remainder of the molecule is attached; R₁ is H, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl or mono or bicyclic saturated heterocycles, optionallysubstituted cycloalkyl, optionally substituted alkenyl, optionallysubstituted alkynyl with the proviso that neither the double bond northe triple bond should be present at the carbon atom which is directlylinked to N; optionally substituted perfluoroalkyl, —S(O)_(p) optionallysubstituted alkyl or aryl where p is 0-2, optionally substituted—C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted—C═Oalkyl, optionally substituted —C═Ocycloalkyl, optionally substituted—C═O mono or bicyclic saturated heterocycles, optionally substitutedC1-C6 alkylaryl, optionally substituted C1-C6 alkylheteroaryl,optionally substituted aryl-C1-C6alkyl, optionally substitutedheteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl,optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substitutedaryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionallysubstituted aryloxyaryl, optionally substituted aryloxyheteroaryl,optionally substituted C1-C6alkylaryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substitutedalkylaryloxyalkylamines, optionally substituted alkoxycarbonyl,optionally substituted aryloxycarbonyl, or optionally substitutedheteroaryloxy carbonyl; R₂ is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substitutedC2-C6 alkynyl, halogen, cyano, N—R₆R₇, optionally substituted C1-C6alkoxy, hydroxy; optionally substituted aryl, optionally substitutedheteroaryl, COOR₆, optionally substituted alkylaryloxyalkylamines,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, optionallysubstituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl,S(O)_(q)-optionally substituted C1-C6 akyl, S(O)_(q)— optionallysubstituted aryl where q is 0, 1 or 2, CONR₆R₇, guanidino or cyclicguanidino, optionally substituted alkylaryl, optionally substitutedarylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionallysubstituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkylmono or bicyclic saturated heterocycles, optionally substitutedarylalkenyl of 8 to 16 carbon atoms, SO₂NR₆R₇, optionally substitutedarylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, optionally substituted aryloxyaryl,optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl,optionally substituted C1-C6alkyl aryloxyaryl, optionally substitutedC1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₆ and R₇ are independently H, optionallysubstituted C1-C6 alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C1-C6 alkyl aryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and Y₁, Y₂, Y₃ and Y₄ are independently C or N.
 37. Themethod according to claim 22 wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄ and Z₅ are independently CR₂, N, O, S or N—R₁provided that one of Z₁-Z₅ is a carbon atom to which the remainder ofthe molecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N;W₁, W₂, W₃ are independently CR₄R₄ O, N—R₁, or S═(O)_(r) (r=0-2) withthe proviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1-4.
 38. The method according to claim 22 whereinthe tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ are independently CR₂, N, O, S or N—R₁provided one of Z₁-Z₆ is a carbon atom to which the remainder of themolecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N; W₁, W₂and W₃ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 3. 39. The method according to claim 22wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇ and Z₈ are independently CR₂, N, O, Sor N—R₁ provided one of Z₁-Z₈ is a carbon atom to which the remainder ofthe molecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N;W₁, and W₂ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁ with theproviso that no S—S, S—O or O—O bond formation can occur to form asaturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; and t=1 to
 2. 40. The method according to claim 22wherein the tricyclic heteroaryl group is

wherein Z₁, Z₂, Z₃ and Z₄ are independently CR₂, N, O, S or N—R₁provided one of Z₁-Z₄ is a carbon atom to which the remainder of themolecule is attached; Y₁, Y₂, Y₃ and Y₄ are independently C or N; W₁,W₂, W₃, W₄ and W₅ are independently CR₄R₄, S(O)r (r=0-2), O, or N—R₁with the proviso that no S—S, S—O or O—O bond formation can occur toform a saturated ring; R₁ is H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl or mono or bicyclicsaturated heterocycles, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl with the provisothat neither the double bond nor the triple bond should be present atthe carbon atom which is directly linked to N; optionally substitutedperfluoroalkyl, —S(O)_(p) optionally substituted alkyl or aryl where pis 0-2, optionally substituted —C═Oheteroaryl, optionally substituted—C═Oaryl, optionally substituted —C═Oalkyl, optionally substituted—C═Ocycloalkyl, optionally substituted —C═O mono or bicyclic saturatedheterocycles, optionally substituted C1-C6 alkylaryl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedaryl-C1-C6alkyl, optionally substituted heteroaryl-C1-C6alkyl,optionally substituted C1-C6 alkyl mono or bicyclic saturatedheterocycles, optionally substituted arylalkenyl of 8 to 16 carbonatoms, —CONR₆R₇, —SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted -alkyl-O-alkyl-aryl, optionally substituted-alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl,optionally substituted heteroaryloxyalkyl, optionally substitutedaryloxyaryl, optionally substituted aryloxyheteroaryl, optionallysubstituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines,optionally substituted alkoxycarbonyl, optionally substitutedaryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl; R₂ ishydrogen, optionally substituted C1-C6 alkyl, optionally substitutedC2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano,N—R₆R₇, optionally substituted C1-C6 alkoxy, hydroxy; optionallysubstituted aryl, optionally substituted heteroaryl, COOR₆, optionallysubstituted alkylaryloxyalkylamines, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C3-C6alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6alkylamino-C1-C6 alkoxy, alkylenedioxy, optionally substitutedaryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O)_(q)-optionallysubstituted C1-C6 akyl, S(O)_(q)— optionally substituted aryl where q is0, 1 or 2, CONR₆R₇, guanidino or cyclic guanidino, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted C1-C6 alkylheteroaryl, optionally substitutedheteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono orbicyclic saturated heterocycles, optionally substituted arylalkenyl of 8to 16 carbon atoms, SO₂NR₆R₇, optionally substituted arylalkyloxyalkyl,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxyalkyl, optionally substituted aryloxyaryl, optionallysubstituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionallysubstituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxyalkyl, or optionally substitutedalkylaryloxyalkylamine; R₄ is H, optionally substituted C1-C6 alkyl, OH(provided both R₄ are not OH), C1-C6 alkoxy, —S—C1-C6 alkyl, COOR₆,—NR₆R₇, —CONR₆R₇; or R₄R₄ may together be ═O or R₄R₄ together with thecarbon to which they are attached may form a spiro system of five toeight members with or without the presence of heteroatoms selected N, O,S(O)_(n) (where n=0 to 2), N—R₁; R₆ and R₇ are independently H,optionally substituted C1-C6 alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R₆and R₇ can be together to form a 3-7 membered saturated ring systemoptionally having one or two heteroatoms selected from N—R₁, O, andS(O)_(n) n=0-2; t=1 to 3; and u=1 to
 3. 41. The method according toclaim 22 wherein the compound has the formula

and wherein X is S.
 42. The method according to claim 22 wherein X is S.43. The method according to claim 22 wherein the compound is selectedfrom the group consisting of a.(5R,6Z)-6-(Imidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; b.(5R,6Z)-6-[(7-methoxyimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; c.(5R,6Z)-6-[(7-chloroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; d. (5R),(6Z)-6-Imidazo[1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; e. (5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; f. (5R),(6Z)-6-(Imidazo[1.2-a]quinoxaline-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hepto-2-ene-2-carboxylicacid, sodium salt; g.(5R,6Z)-6-[(7-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; h. (5R),(6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopentafa]indene-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid sodium salt; i.(5R,6E)-6-[(10-benzyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-8-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; j.6-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid; k. (5R,6E&Z)-7-oxo-6-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; l. (5R),(6Z)-6-(5H-Imidazo[2,1-a]isoindol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylicacid sodium salt; m.(5R,6Z)-6-[(5-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; n.(5R,6Z)-6-[(7-fluoroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; o.(5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; p. (5R),(6Z)-6-(imidazo[2,1-b]bebzothiazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; q. (5R),(6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; r.(5R),(6Z)-6-(7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-ylmethylene)-7-oxo-6-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; s. (5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; t. (5R),(6Z)-8-[(9-methyl-9H-imidazo[1,2-a]benzimidazol-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid; u.(5R,6Z)-7-oxo-6-(4H-thieno[2′,3′:4,5]thiopyrano[2,3-b]pyridin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid (Sodium salt); v.(5R,6Z)-6-[(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; w.(5R,6Z)-6-{[7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; x.(5R,6Z)-6-(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolo[1,5-a]quinazolin]-2′-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid,sodium salt; y.(5R,6Z)-6-[(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; z.(5R,6Z)-6-[(5-methoxy-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; aa.(5R,6Z)-6-({5-[2-(benzyloxy)ethoxy]-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl}methylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; bb.(5R,6Z)-6-(2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; cc.(5R,6Z)-6-(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; dd.(5R,6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; ee.(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; ff.(5R,6Z)-7-oxo-6-(5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazol-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt; and gg.(5R,6Z)-6-{[6-(ethoxycarbonyl)-5,6,7,8-tetrahydropyrazolo[5′,1′:2,3][1,3]oxazolo[5,4-c]pyridin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt.
 44. A pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound as defined in claim 1 or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof.